Serum thrombopoietin levels in patients with chronic hepatitis and liver cirrhosis

OBJECTIVE: Thrombocytopenia is a common manifestation of cirrhosis. The aim of this study was to examine the relationship between serum thrombopoietin concentrations, circulating platelet levels, and the stage of hepatic fibrosis in patients with chronic viral hepatitis. METHODS: The study included 48 patients with chronic viral hepatitis (14 with stage 1 fibrosis; five with stage 2 fibrosis; three with stage 3 fibrosis; 26 with cirrhosis) and 30 healthy volunteers. Serum thrombopoietin levels were measured using an enzyme-linked immunosorbent assay. Spleen size, platelet counts, and prothrombin time were measured. RESULTS: Thrombopoietin levels of patients with fibrosis stage 1 (2.50 +/- 1.60 fmol/ml) or stage 2 (1.89 +/- 0.65) were significantly higher than those in patients with cirrhosis (1.21 +/- 0.55) or healthy volunteers (1.26 +/- 0.74). Mean platelet counts of patients with cirrhosis (8.0 +/- 4.6 x 10(4)/microl) were significantly lower than those with fibrosis stage 1 (18.6 +/- 3.9) or stage 2 (16.0 +/- 5.8), or healthy volunteers (24.5 +/- 7.3). Patients with cirrhosis had larger spleens (30.9 +/- 18.4 cm2) than those with fibrosis stage 1 (18.2 +/- 6.4). Platelet counts showed a significant inverse relationship to spleen size (p = -0.51, p < 0.0005) and a significant positive relationship with thrombopoietin levels (p = 0.34, p < 0.02). Thrombopoietin levels were significantly correlated to prothrombin time (p = 0.45, p < 0.005). CONCLUSIONS: Serum thrombopoietin levels are elevated in patients with an early stage of chronic viral hepatitis. As the disease progresses from mild fibrosis to cirrhosis, decreased production of thrombopoietin may contribute to the further development of thrombocytopenia in cirrhosis.     

Extracapillary IgA nephropathy associated with infection with hepatitis C virus and hepatic cirrhosis

We describe a 36 year old man who was admitted to the hospital with dyspnea, edema of the lower limbs, arterial hypertension and oliguric renal failure. He had microhematuria and nephrotic range proteinuria, immunological tests were normal or negative. Renal biopsy revealed global (55%) or segmental glomeruloesclerosis, remaining glomeruli showed extracapillary proliferation (25%). Immunofluorescence study disclosed IgA mesangial deposits. He was also diagnosed as having liver cirrhosis with positive serology against hepatitis C virus. He was treated with dialysis, antihypertensive drugs and steroids with improvement of the renal function. However, ten months later maintenance hemodialysis became necessary. We emphasize two points: first IgA glomerulonephritis is rarely associated with hepatitis C infection, and second crescentic IgA nephropathy has been infrequently reported in liver cirrhosis.     

Chronic viral C hepatitis associated with primary biliary cirrhosis. Report of two cases

Chronic viral hepatitis C is often associated with various autoimmune disorders. We report two patients infected by genotype 1b hepatitis C virus associated with primary biliary cirrhosis. These patients had anicteric cholestasis associated with cytolysis and positivity of M2 antimitochondrial antibodies at a titre of 1/200. Liver biopsy revealed chronic hepatitis in one case and histological pattern of primary biliary cirrhosis in the other. One patient was treated by antiviral therapy; the other only by ursodesoxycholic acid because of the association with hemolytic anemia. Association between primary biliary cirrhosis and chronic viral hepatitis C is uncommon and associated with diagnostic and therapeutic challenges.     

Antiviral therapy of decompensated cirrhosis due to hepatitis C viral infection.

BACKGROUND: For decompensated HCV cirrhosis, liver transplantation is the only available treatment. Only a few studies in world literature have used antiviral therapy in this situation. METHODS: During a 4-year period, we gave closely monitored antiviral therapy to all consecutive patients of HCV-related cirrhosis with episodes of decompensation. Patients who were excluded from the standard Interferon trials were treated. Patients were started on low dose Interferon alpha-2b (1 MIU tiw) and Ribavirin (800 mg/day) combination therapy or low-dose Interferon alpha- 2b (1 MIJ tiw) monotherapy (in the presence of renal failure) for 6 months to 1 year. Dose of Interferon was escalated gradually to a maximum dose of 3 MIU tiw according to clinical follow-up. RESULTS: A total of 18 patients (mean age = 51.6 +/- 9.8 years; male: female ratio= 10: 8) were treated. At baseline, mean Child-Pugh score was 9.4 +/- 0.8 (range = 7-12). Interferon monotherapy was given to 4 (22.2%) and combination therapy to 14 (77.8%) patients after clinical recovery from an episode of decompensation. Though 16 (88.9%) patients noticed some adverse events, 15 (83.3%) patients completed the treatment schedule. Premature discontinuation was warranted in 3 (16.7%) patients. Out of the 15 patients who completed the treatment schedule, mean maximum tolerated dose of Interferon was 1.73 +/- 0.6 MIU tiw, 10 patients had genotype II or III and 2 patients had genotype I. Of these, end-of-treatment virological response was seen in 11 (73.3 %) and sustained virological response (at 6 months) in 7 (46.6 %) patients. All these patients were followed up for a mean duration of 1.3 +/- 0.6 years (6 month to 3.5 years). During follow up, 7 non-responders had further episodes of decompensation, of whom 4 died. CONCLUSION: Although there is high intolerance to the treatment, closely-monitored low dose escalating Interferon and/ or Ribavirin therapy achieves good results.     

The role of thrombopoietin in the thrombocytopenia of patients with liver cirrhosis

OBJECTIVES: Thrombocytopenia is a common disorder among cirrhotics that has been traditionally explained by splenic platelet pooling and destruction. Thrombopoietin (TPO), the main stimuli for thrombopoiesis is produced primarily in the liver and degraded by circulating platelets, but its role in the thrombocytopenia of liver cirrhosis is not well understood. The main goal of this study is to clarify the role of TPO in the pathogenesis of thrombocytopenia in cirrhosis. METHODS: The relation among TPO, platelet count, spleen size, portal hypertension, and liver function was studied in 33 cirrhotic patients before and after either partial splenic embolization or liver transplantation. RESULTS: Cirrhotics with thrombocytopenia had lower serum TPO levels than healthy controls (median values (interquartile range: ICR) were 120.7 (42.0-191.6) vs 756.4 (527.0-965.1) pg/mL, respectively; p<0.001). Among cirrhotics with thrombocytopenia, serum TPO was related to spleen size (rho=-0.387, p=0.046), but not to platelet count as occurs physiologically. After partial splenic embolization, TPO and platelet count increased significantly and the physiological relation between TPO and platelet count was restored (rho=-0.665, p=0.026). Similar results were observed after liver transplantation. CONCLUSIONS: Our results suggest that besides impaired production in the failing liver, an increased TPO degradation by platelets sequestered in the congested spleen may contribute to thrombocytopenia in cirrhotic patients.     

Concise review: Interferon-free treatment of hepatitis C virus-associated cirrhosis and liver graft infection

Chronic hepatitis C is a major reason for development of cirrhosis and hepatocellular carcinoma and a leading cause for liver transplantation. The development of direct-acting antiviral agents lead to (pegylated) interferon-alfa free antiviral therapy regimens with a remarkable increase in sustained virologic response (SVR) rates and opened therapeutic options for patients with advanced cirrhosis and liver graft recipients. This concise review gives an overview about most current prospective trials and cohort analyses for treatment of patients with liver cirrhosis and liver graft recipients. In patients with compensated cirrhosis Child-Pugh-Turcotte (CTP) class A, all approved agents are safe and SVR rates do not significantly differ from patients without cirrhosis in general. In patients with decompensated cirrhosis CTP class B or C, daclastasvir, ledipasvir, velpatasvir, and sofosbuvir are approved, and SVR rates higher than 90% can be achieved. Especially for patients with a model of end stage liver disease score higher than 15 and therefore eligible for liver transplantation, data is scarce. Reported SVR rates in patients with cirrhosis CTP class C are lower compared to patients with a less severe liver disease. In liver transplant recipients with a maximum of CTP class A, SVR rates are comparable to patients without LT. Patients with decompensated graft cirrhosis should be treated on an individual basis.     

The systemic and local immune responses in patients with alcoholic liver cirrhosis depending on hepatitis C viral infection (HCV)

The systemic and local immune response was studied in patients with alcoholic liver cirrhosis and the significance of the combined infection with HCV. To investigation were submitted 23 patients (16 males and 7 females) aged between 29 and 61 years with alcoholic liver cirrhosis. Of them 14 were anti-HCV(+) and 9 anti-HCV(-). As controls were used 36 clinically healthy individuals, matched by sex and age to the patients. The flow cytometric analysis of the lymphocyte (Ly) populations from the peripheral venous blood and of cells from liver aspirate obtained by blind liver biopsy according to Menghini, was performed with FacsTAR (Becton Dickinson). In the anti-HCV(-) patients, as compared to the controls (patients/controls) the Ly subpopulations were increased: CD3+/mm3:2010 +/- 738/1440 +/- 388; CD4+/mm3:1350 +/- 441/991 +/- 442; IL-2R+/mm3:133 +/- 78.5/31 +/- 20. In the anti-HVC(+) patients we established increased IL-2R+/mm3: 170 +/- 126 as compared with the controls and anti-HCV(-) patients. The suppressor/cytotoxic (CD8+) Ly with their suppressor (CD8+CD11b+) and cytotoxic (CD8+CD11b-) subpopulations and natural killers (CD16+) had a tendency to diminution in the anti-HCV(+) patients. In both examined groups the B (CD19+) Ly were non-significantly increased. The flow cytometric analysis of the cells from the liver specimen in 9 patients of whom 3 anti-HCV(-) and 6 anti-HCV(+) revealed that CD3+ on the average were 32.8% +/- 20.4% (from 9.2% to 65.1%); CD4+ were 21.1% +/- 7.4% (from 12.0% to 34.5%); CD8+ 22.6% +/- 11.8% (from 4.7% to 39.8%) and their values were higher in the anti-HCV(+) patients; the correlation CD4+/CD8+ = 1/1.09 +/- 0.6; CD16+ were 12.9% +/- 10.1% (from 1.9% to 34.8%); CD19+ varied from 3.2% to 27.8%; monocytes (CD14+) were 7.69% +/- 5.65 (from 2.0% to 15.8%) from the cells of the aspirate and their percentage contents was higher in the anti-HCV(+) patients. The results of out study revealed that in patients with alcoholic liver cirrhosis changes in the cell immune response were also observed and that they were more marked in infection with HCV.     

Relationship between thrombopoietin serum levels and liver function in patients with chronic liver disease related to hepatitis C virus infection

OBJECTIVES: Thrombopoietin (Tpo) is an important regulator of megakaryocyte maturation and platelet production, and is mainly produced by the liver. A decrease in Tpo production is partly responsible for the thrombocytopenia observed in patients with chronic liver disease (CLD). The aim of this study was to evaluate the relationship between Tpo serum levels and liver function in patients with CLD related to hepatitis C virus (HCV) infection. METHODS: We studied 37 patients with various degrees of HCV-related CLD. Of the patients, 17 had chronic hepatitis and 20 liver cirrhosis. Liver function was evaluated in all patients by the following hepatic blood flow dependent and independent tests that explore various hepatic metabolic functions: carbon-13 (13C)-aminopyrine breath test (13C-ABT), 13C-galactose breath test (13C-GBT), and monoethylglycinexylidide (MEGX) test. Liver function tests results were correlated with Tpo serum levels. RESULTS: Tpo serum levels were significantly lower in patients with liver cirrhosis (88 +/- 23 pg/ml) as compared to those in patients with chronic hepatitis (128 +/- 55 pg/ml, p=0.0031). However, they did not correlate with serum albumin, bilirubin, or prothrombin activity. Tpo serum levels showed a significant positive correlation with 13C-ABT results (hourly dose at 30 min, rs=0.489, p=0.002; cumulative dose at 120 min, rs=0.425, p=0.008). Moreover, they showed a fair, positive correlation with 13C-GBT hourly dose at 30 min (rs=0.366, p=0.028), and a trend toward a positive correlation with the various MEGX test sampling times (MEGX15, rs=0.314, p=0.059; MEGX30, rs=0.284, p=0.088; and MEGX60, rs=0.320, p=0.059). CONCLUSIONS: In this study we have shown that a progressive decline in liver function in patients with HCV-related CLD is paralleled by a decrease in Tpo production. The different correlations observed between Tpo and the various liver function tests suggests that this finding is mainly the result of a decrease in hepatic functional mass rather than dependent on alteration in splanchnic hemodynamic.     

Recurrent and acquired hepatitis C viral infection in liver transplant recipients.

To examine the postliver transplant recurrence of hepatitis C virus (HCV) infection in patients with pretransplant infection, as well as its acquisition in patients without prior infection, we used the polymerase chain reaction to amplify HCV RNA in serum and/or liver samples of 89 patients with alcoholic and cryptogenic cirrhosis undergoing liver transplantation. Results were correlated with histologic findings from posttransplant liver biopsies. Ninety-five percent of patients with pretransplant infection had posttransplant viremia. In contrast, 35% of patients without pretransplant infection acquired the virus (P less than 0.0001). Pretransplant HCV infection predisposed patients to hepatitis in the new graft. HCV RNA was present in serum of 96% of patients with posttransplant hepatitis. Fifty-six percent of patients with posttransplant HCV infection had no evidence of liver damage at least 1 year posttransplant. However, of those patients with histologic hepatitis, chronic active hepatitis was common. It is concluded that although HCV infection recurs posttransplant in almost all infected patients, acquisition of the HCV infection with transplant is common. Pretransplant HCV infection is an independent risk factor for the development of posttransplant hepatitis. HCV infection accounts for the majority of posttransplant hepatitis not due to cytomegalovirus, and although many patients with posttransplant viremia have little evidence of histologic hepatitis, significant hepatic damage may occur.     

Cryoglobulinemia following liver transplantation for cirrhosis secondary to hepatitis C virus infection

Hepatitis C virus (HCV) infection has been linked with some extrahepatic immunologic abnormalities. Cryoglobulinemia is one of the most frequently reported. Nevertheless, there are only a few reports of cryoglobulinemia in the setting of liver transplantation. More studies are needed to clarify the frequency of post-OLT cryoglobulinemia in patients with HCV-related cirrhosis and its impact on OLT outcome. A case of a patient who underwent liver transplantation because of HCV end-stage liver disease and in whom cryoglobulinemia appeared 3 years after transplantation is reported. Treatment with cyclophosphamide and steroids was attempted but patient died of septicemia 3 years after liver transplantation.     

Serum leptin levels in patients with liver cirrhosis and chronic viral hepatitis

BACKGROUND: The aim of the present study was to investigate serum leptin levels in relation to anthropometric features in patients with liver cirrhosis (LC) and chronic viral hepatitis (CVH), and to determine the effect of the severity and aetiology of the LC on serum leptin levels. METHODS: Forty-nine patients with LC, 32 patients with CVH and 69 control subjects were age, body mass index (BMI) and sex-matched and included in the study. Plasma glucose, serum leptin and insulin levels were determined. Insulin resistance was assessed using homoeostasis model assessment (HOMA). Body composition was estimated by skinfold thickness. RESULTS: Female patients with Child-A LC had higher levels of leptin, and female and male patients with Child-A LC had higher absolute leptin (leptin/BFM) levels compared to patients with Child-C LC and control subjects. Serum leptin levels of the patients with alcohol LC were higher than the control subjects, but the absolute leptin levels were comparable. When alcoholic and post-viral hepatitis cirrhotic patients were compared with each other on an aetiologic basis, there was no significant difference between them in leptin and absolute leptin levels. There were significant correlations between leptin and BMI, body fat percentage (BFP), BFM (body fat mass) in all three groups in both sexes. CONCLUSIONS: These data suggest that the physiologic correlations among serum leptin level, sex, BMI and BFM were well preserved in patients with chronic liver disease. Patients with alcohol LC had higher leptin levels. In early stages of liver disease, leptin levels and absolute leptin levels are higher than in normal subjects. However, in advanced stages of the disease the significant decline in leptin levels and similar levels of leptin expressed in relation to BFM compared to control subjects predominantly represent the expression of fat mass.     

Progastrin and its products from patients with chronic viral hepatitis and liver cirrhosis

BACKGROUND: Gastrin and its precursor, progastrin, are synthesized in the stomach, particularly when infected with Helicobacter pylori, and they are metabolized, at least in part, in the liver. However, little is known about their levels in various hepatic diseases. METHODS: This study was carried out on 147 patients including chronic hepatitis B (n = 35), hepatitis C (n = 52) and liver cirrhosis (n = 60) of class A (n = 38), class B (n = 15) and class C (n = 7) (Child-Pugh classification) and age- and sex-matched healthy controls (n = 65). The diagnosis of chronic hepatitis was confirmed by liver biopsy in all patients, whereas the diagnosis of liver cirrhosis was based on clinical and laboratory findings. Liver biopsy was done in 38 out of 60 patients. Blood samples were collected under basal conditions and separated plasma samples were kept frozen at -70 degrees C until radioimmunoassay of progastrin and its products, including bioactive amidated gastrins. RESULTS: Median (range) plasma concentrations of total progastrin product and amidated gastrin in control subjects were 147.5 (73-345) pM and 33 (15-65), respectively. These concentrations in hepatitis B and C were not significantly different from those in controls. In cirrhosis (classes A, B and C), the concentrations of the progastrin and of gastrin were significantly (P < 0.05) higher than in controls reaching, respectively, 253.5 (135-683 pM) and 47.5 (17-385) pM. Both progastrin and gastrin levels were significantly higher in H. pylori-positive than in negative cirrhotic patients. Antibodies against H. pylori were present in about 50% of controls, 68% of hepatitis B, 57% of hepatitis C and in 83% in cirrhosis patients. The difference in H. pylori prevalence between cirrhosis and controls was statistically significant. CONCLUSIONS: Plasma levels of progastrin and gastrin are significantly increased in cirrhotic patients and this could be attributed to reduced metabolism of these peptides in liver cirrhosis and to their increased release due to H. pylori infection rate in this disease.