Procalcitonin, and cytokines document a dynamic inflammatory state in non-infected cirrhotic patients with ascites.

AIM: To quantitate the simultaneous serum and ascitic fluid levels of procalcitonin and inflammatory markers in cirrhotics with and without ascites. METHODS: A total of 88 consecutive severe cirrhotic patients seen in a large city hospital liver clinic were studied and divided into two groups, those with and without ascites. Group 1 consisted of 41 cirrhotic patients with massive ascites, as demonstrated by necessity for therapeutic large-volume paracentesis. Group 2 consisted of 47 cirrhotic patients without any clinically documented ascites to include either a recent abdominal computed tomography scan or ultrasound study. Serum and ascitic fluid levels of an array of inflammatory markers, including procalcitonin, were measured and compared to each other and a normal plasma panel (NPP). RESULTS: The values for inflammatory markers assayed in the serum of Groups 1 and 2, and ascitic fluid of the Group 1. The plasma levels of the inflammatory cytokines interleukin (IL)-2, IL-4, IL-6, IL-8, interferon gamma (IFNγ) and epidermal growth factor (EGF) were all significantly greater in the serum of Group 1 as compared to that of the serum obtained from the Group 2 subjects (all P < 0.05). There were significantly greater serum levels of IL-6, IL-8, IL-10, monocyte chemoattractant protein-1, tumor necrosis factor-α, vascular endothelial growth factor and EGF when comparing Group 2 to the NPP. There was no significant difference for IL-1A, IL-1B, IL-2, IL-4 and IFNγ levels between these two groups. Serum procalcitonin levels were increased in cirrhotics with ascites compared to cirrhotics without ascites, but serum levels were similar to ascites levels within the ascites group. Furthermore, many of these cytokines, but not procalcitonin, demonstrate an ascites-to-serum gradient. Serum procalcitonin does not demonstrate any significant difference segregated by liver etiology in the ascites group; but ascitic fluid procalcitonin is elevated significantly in cardiac cirrhosis/miscellaneous subgroup compared to the hepatitis C virus and alcoholic cirrhosis subgroups. CONCLUSION: Procalcitonin in the ascitic fluid, but not in the serum, differentiates between cirrhotic subgroup reflecting the dynamic interplay of ascites, bacterial translocation and the peri-peritoneal cytokine.

Disease dependent qualitative and quantitative differences in the inflammatory response to ascites occurring in cirrhotics.

AIM: To assess differing patterns and levels of ascitic fluid cyctokine and growth factors exist between those with a high risk and low risk of spontaneous bacterial peritonitis (SBP). METHODS: A total of 57 consecutive patients with ascites requiring a large volume paracentesis were studied. Their age, gender, specific underlying disease conditions were recorded after a review of their clinical records. Each underwent a routine assessment prior to their paracentesis consisting of a complete blood count, complete metabolic profile and prothrombin time/international normalized ratio (INR) determination. The ascitic fluid was cultured and a complete cell count and albumin determination was obtained on the fluid. In addition, blood and ascitic fluid was assessed for the levels of interleukin interleukin (IL)-1A, IL-1B, IL-2, IL-4, IL-8, IL-10, monocyte chemotactic protein (MCP)-1, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) utilizing the Randox Biochip platforms (Boston, MA). A serum-ascites gradient, for each cytokine and growth factor was calculated. The results are reported as mean ± SEM between disease groups with statistical analysis consisting of the student t-test (two tailed) with a P value of 0.05 defining significance. RESULTS: No clinically important demographic or biochemical differences between the 4 groups studied were evident. In contrast, marked difference in the cytokine and growth factors levels and pattern were evident between the 4 disease groups. Individuals with alcoholic cirrhosis had the highest levels of IL-1A, IL-1B, IL-4, IFNγ. Those with malignant disease had the highest levels of IL-2. Those with hepatitis C virus (HCV) associated cirrhosis had the highest value for IL-6, IL-8, IL-10, MCP-1 and VEGF. Those with cardiac disease had the highest level of TNF-α and EGF. The calculated serum- ascites gradients for the cardiac and malignant disease groups had a greater frequency of negative values signifying greater levels of IL-8, IL-10 and MCP-1 in ascites than did those with alcohol or HCV disease. CONCLUSION: These data document important differences in the cytokine and growth factor levels in plasma, ascitic fluid and the calculated plasma - ascites fluid gradients in cirrhotics requiring a large volume paracentesis. These differences may be important in determining the risk for bacterial peritonitis.

Plasma triglyceride levels may modulate hepatitis C viral replication.

BACKGROUND: Plasma and hepatic lipid abnormalities are frequent in hepatitis C infected individuals. METHODS: Plasma lipid and medical records profiles were prospectively obtained in 130 consecutive individuals seen by a single hepatologist in a university liver disease clinic. The relationships between viral load, genotype, plasma lipid fractions, HDL, LDL particle number and particle size were examined. RESULTS: Of 130 individuals studied, 74 had hepatitis C while 15 had NAFLD/NASH and 30 had alcohol related liver disease. The LDL particle number and LDL-C levels did not differ between those with and without hepatitis C although the number of small LDL particles was greater in those with hepatitis C infection. The HDL-C and total cholesterol levels were greater in those without hepatitis C than those with hepatitis C (P = 0.009). In contrast, the serum triglyceride level was greater in the hepatitis C viral group (P = 0.013). Importantly, the hepatitis C viral load regardless of the genotype correlated directly with the triglyceride and VLDL levels with r values of 0.73 and 0.84, respectively. CONCLUSIONS: There are: (1) important differences in lipid classes, number and the size of lipid particles exist between hepatitis C virus infected and noninfected liver disease groups, (2) the serum total triglyceride and the LDL levels correlate significantly with the hepatitis C viral load and, (3) Serum triglyceride level may play an important role in viral replication. These data further suggest that therapies directed at lowering plasma triglyceride levels may enhance the efficacy of current antiviral treatment regimens.

Fungal infections: their diagnosis and treatment in transplant recipients.

Systemic fungal infections typically occur in individuals who are seriously ill with recognized risk factors such as those frequently found in transplant recipients. Unfortunately, they are often diagnosed late, when the efficacy of the available treatments is low, often less than 50%, and the cost in terms of lives lost, hospital length of stay, and total hospital costs is substantially increased. The application of antifungal therapies associated with reported efficacy rates greater than 50% are those used prophylactically. When used prophylactically, these infections are reduced in greater than 95% of the expected cases. The choice of a prophylactic agent should be based upon its ease of administration, lack of adverse effects, reduced likelihood of potential drug interactions, and its efficacy in patients with established risk factors and comorbid disease processes that include renal, hepatic, and chronic pulmonary disease. The indications for the use of currently available antifungal agents, their adverse effects, drug interactions, ease of dosing, and applicability in patients with preexisting disease states, and especially in liver transplant recipients, are presented in this paper.

Consensus interferon used to treat prior partial-responders to pegylated interferon plus ribavirin.

BACKGROUND: The response to pegylated interferon (peg-IFN) plus ribavirin therapy remains less than ideal with 40-50% of treated subjects failing to clear the virus. Moreover, retreatment is only minimally effective. Consensus interferon (c-IFN) has been shown to be efficacious in HCV genotype 1 patients who have failed therapy with peg-IFN. AIM: To evaluated the response to re-treatment of peg-IFN plus ribavirin partial-responders with c-IFN plus ribavirin. METHODS: Forty-two subjects who had previously failed to clear virus after treatment with peg-IFN plus ribavirin were treated with c-IFN (15 µg/day) plus ribavirin (800-1,200 mg/day) until 12 months of therapy or a total of six consecutive months of PCR negativity was achieved. RESULTS: The study population consisted predominantly of males (71%), Caucasians (76%), with African Americans comprising the remaining 24%, subjects with HCV genotype 1 infection (81%) and 21% had cirrhosis by liver biopsy. The overall SVR rate was 29%. The only pretreatment variable that distinguished responders from partial-responders was the serum triglyceride level. CONCLUSIONS: The use of c-IFN plus ribavirin in the retreatment of prior peg-IFN plus ribavirin partial responders is essentially twice that achieved in prior re-treatment regimens consisting of a second course of peg-IFN plus ribavirin. These results will need to be evaluated against the use of triple therapy consisting of a peg-IFN plus ribavirin and a protease inhibitor. More studies utilizing c-IFN plus ribavirin with either a protease inhibitor or polymerase inhibitor need to be performed as well.

Continuous peritoneal drainage of large-volume ascites.

BACKGROUND: With the increasing population of individuals with cirrhosis, many of whom are not liver transplant candidates, large volume paracentesis as a medical therapy for ascites resistant to diuretic therapy has become increasingly utilized. AIM: To determine the safety and efficacy of continuous peritoneal drainage of large-volume ascites in Child Class-C cirrhosis. Subjects with no current clinical or laboratory findings of spontaneous bacterial ascites were studied. Each had a complete medical evaluation to document the etiology and severity of their liver disease as well as the identification of any confounding medical illness. A triple-phase abdominal CT of the abdomen was obtained in each individual to rule out any hepatoma. Upon completion of the above, a pericardiocentesis catheter was placed in the abdomen using the Seldinger technique and the ascites was drained continuously (to gravity) until no additional ascitic fluid could be removed or the total time of drainage was 72 h. The patient's weight, volume of ascitic fluid removed, ascitic fluid cell counts, ascitic fluid cultures, complete blood count and comprehensive metabolic profile were obtained immediately before and after the peritoneal catheter was removed. RESULTS: HCV cirrhosis accounted for 12 cases and alcoholic liver disease accounted for 8 cases (half the total of 40 cases), with 6 other diseases accounting for the remaining half. The ascitic fluid was drained continuously for 2.5 ± 0.08 days, with a removal of 13.3 ± 0.5 l of ascitic fluid. No clinically significant change in the serum creatinine or ascitic fluid cells count occurred as a result of the procedure. The adverse effects of the procedure were minimal. 63% of the patients experienced some mild discomfort at the catheter insertion site, or local abdominal pain just prior to the removal of the catheter. Two patients developed a small abdominal wall hematoma that required no therapy. No patients experienced peritoneal hemorrhage, infection or renal dysfunction. CONCLUSION: (1) Continuous large-volume peritoneal drainage by gravity is safe and effective; (2) if the procedure is limited 72 h, no cases of ascitic fluid contamination/infection occur; and (3) it reduces the time between subsequent paracentesis based upon historical data.

Use of recombinant factor VIIa to correct the coagulation status of individuals with advanced liver disease prior to a percutaneous liver biopsy.

OBJECTIVES: Percutaneous liver biopsies are used to grade and stage liver disease and are also useful in monitoring the progress of liver disease over time as well as the response to medical therapies. The present study was undertaken to assess the effectiveness of recombinant factor VIIa as a means of transiently correcting the coagulopathy, enabling the safe performance of a percutaneous liver biopsy in patients in whom the use of fresh-frozen plasma is not possible without precipitating pulmonary edema or who have a treatment induced (iatrogenic) coagulopathy. METHODS: The subjects of this report consisted of 18 consecutive individuals with advanced disease induced, and 15 with a therapeutic iatrogenic-induced, coagulopathy. All biopsies were performed by a single hepatologist. Before and 6 h after each biopsy, a prothrombin time and partial thromboplastin time was obtained from each subject. Mean values +/- the standard error of the mean were obtained using the independent samples T-test. RESULTS: Recombinant factor VIIa had a marked effect in transiently correcting the mean prothrombin time in these subjects allowing for a safe complication free percutaneous biopsy in this high-risk group. CONCLUSIONS: Recombinant factor VIIa could be used to obtain a clinically indicated liver biopsy in severely ill patients, who without this therapeutic agent, would either not be biopsied or, if biopsied, would require much longer hospitalization and the use of fresh-frozen plasma (with its risks of volume overload and infection).

Antiphospholipid antibodies before and after liver transplantation.

OBJECTIVE: The aim of this study was to determine whether liver transplantation of patients with antiphospholipid antibodies (APA) is 1) adversely affected with vascular thrombosis and 2) whether such antibodies persist post transplantation. METHODS: Twelve patients with APA awaiting transplant were identified and characterized biochemically and immunologically. Each had the level of APA determined using commercially available enzyme-linked immunoassay kits before, during, and after liver transplantation. RESULTS: No patient in this series experienced a transplant-related vascular thrombosis. The titer of APA fell to levels at or below those present in normals and remained low in two of 12 or undetectable in 10 of 12 patients 1 yr after liver transplantation. CONCLUSIONS: We reached the following conclusions: 1) Antiphospholipid positivity does not identify patients at high risk for post-transplant vascular thrombosis. 2) The levels of antiphospholipid present in sera pretransplant fell during transplantation and remained low or undetectable 1 month and 1 yr post transplantation.