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.

Vitamin D status and serum ferritin concentration in chronic hepatitis C virus type 1 infection.

The circulating 25-hydroxylated form of vitamin D(3), 25(OH)D, and serum ferritin concentrations have been described to be associated with disease progression in chronic hepatitis C. Both parameters also have been assessed with regard to treatment outcome, however, with divergent results. This study examined both the pre- and posttreatment serum concentrations of 25(OH)D and ferritin in 191 patients infected chronically with hepatitis C virus (HCV) type 1 with regard to liver inflammatory activity (grading), disease progression in terms of fibrosis (staging) and an antiviral treatment outcome. Mean pretreatment serum 25(OH)D and ferritin concentrations were 18 ± 10 ng/ml and 280 ± 225 µg/L, respectively. Multivariate analysis revealed lower pretreatment serum 25(OH)D and higher ferritin concentrations to be significantly related to both severity of inflammatory activity and of fibrotic alterations. Pretreatment serum ferritin concentration, furthermore, unlike 25(OH)D concentration, was found to be associated with a sustained virological response by uni- and multivariate analyses. A sustained virological response was featured by a significant increase in serum 25(OH)D levels (18 ± 10 ng/ml vs. 22 ± 11 ng/ml; P < 0.01), a reduction of serum ferritin concentration (191 ± 156 µg/L vs. 103 ± 63 µg/L; P < 0.001) and a normalization of serum alanine aminotransferase (ALT) and γ-glutamyl-transferase (γ-GT) activities. Taken together, decreased 25(OH)D and increased ferritin serum levels indicate the severity of hepatic inflammation and fibrosis in patients infected chronically with HCV type 1. Elevated ferritin, furthermore, was found to be an independent predictor for standard IFN-based therapy responsiveness.

Current concepts and management approaches in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver dysfunction worldwide. NAFLD may progress to nonalcoholic steatohepatitis (NASH) and in turn cirrhosis. Importantly, hepatic cancer can occur in NASH in the absence of cirrhosis. The cardinal histologic feature of NAFLD is the presence of an excessive accumulation of triacylglycerols and diacylglycerols in hepatocytes. The presence of obesity and insulin resistance lead to an increased hepatic-free fatty acid (FFA) flux creating an environment appropriate for the development of NAFLD. The generation of toxic reactive oxygen species with the production of hepatic injury and inflammation as a consequence of FFA oxidation will ultimately lead to the initiation and progression of fibrosis. Lifestyle modifications specifically weight loss, physical exercise, and cognitive behavior therapy have been recommended as treatments for NASH. Dietary fructose is an independent risk factor for the development of NAFLD. Pioglitazone can be used to treat biopsy-proven NASH; however, its safety risks should be considered carefully. Greater consumption for coffee, independent of its caffeine component, has been associated with a significant reduced risk of advanced fibrosis in NASH. Additional data are needed before recommending bariatric surgery as an established option for the specific treatment of NASH.

Early anemia and rapid virological response improve the predictive efficiency of IL28B-genotype for treatment outcome to antiviral combination therapy in patients infected with chronic HCV genotype 1.

IL28B genotypes and virological response within 4 weeks are predictors of sustained virological response in patients infected with chronic hepatitis C virus (HCV) genotype 1 treated with antiviral dual combination therapy. The predictive value of "early" anemia (within 4 weeks) alone or in combination with the two other predictors has not been studied yet. A total of 305 pegylated interferon-α and ribavirin-treated patients with HCV genotype 1 were included in this study. Hemoglobin values at week 0, 4, 8, and 12 as well as the predictive efficiency of early anemia (hemoglobin value below the gender-specific lower limit: female < 11.5; male < 13.5 g/dl) during therapy were assessed with IL28B genotypes and rapid virological response. Forty-eight percent of treated patients developed early anemia. In both females and males (64%), a decrease of hemoglobin concentration of 3 g/dl (female: 14.7 ± 1.1 to 11.4 ± 1.3; male: 15.2 ± 1.2 to 12.2 ± 1.5) significantly correlated with sustained virological response. 64% of IL28B-CC patients showed a sustained virological response. Seventy-eight percent of patients with rapid virological response definitively eliminated the virus. Early anemia (81:48:41%) and rapid virological response (83:91:92%) increased the predictive efficiency of IL28B rs12979860 genotype distribution (CC:CT:TT). IL28B-CC and early anemia as well as IL28B-CC and rapid virological response had an Odds ratio of 42.4 or 75 to achieve a sustained virological response compared to TT without early anemia or rapid virological response. This finding may help to early identify responders to standard PEG-IFN-α and ribavirin treatment even within those with unfavorable IL28B genotype.

Endogenous Glycosaminoglycans in Various Pathologic Plasma Samples as Measured by a Fluorescent Quenching Method.

Endogenous glycosaminoglycans (GAGs) with a similar structure to heparin are widely distributed in various tissues. A fluorescence probe, namely Heparin Red, can detect polyanionic GAGs in plasma samples. The purpose of this study is to measure endogenous GAGs in various plasma samples obtained from different pathologic states in comparison to healthy controls utilizing this method. Plasma samples were obtained from patient groups including atrial fibrillation (AF), end-stage-renal-disease (ESRD), diabetes mellitus (DM), sepsis, cancer, liver disease (LD), and pulmonary embolism (PE). Normal human plasma (NHP) was used as healthy controls. The Heparin Red kit from Red Probes (Münster, Germany) was used for the quantification of endogenous GAGs in each sample before and after heparinase I degradation. All results were compiled as group means ± SD for comparison. NHP was found to have relatively low levels of endogenous GAGs with a mean concentration of 0.06 µg/mL. The AF, ESRD, DM, and sepsis patient samples had a mean endogenous GAG concentration of 0.55, 0.72, 0.92, and 0.94 µg/mL, respectively. The levels of endogenous GAGs were highest in cancer, LD, and PE patient plasma samples with a mean concentration of 1.95, 2.78, and 2.83 µg/mL, respectively. Heparinase I degradation resulted in a decline in GAG levels in plasma samples. These results clearly show that detectable Heparin Red sensitive endogenous GAGs are present in circulating plasma at varying levels in various patient groups. Additional studies are necessary to understand this complex pathophysiology.

Transjugular liver biopsy: comparison of sample adequacy with the use of two automated needle systems.

PURPOSE: To compare the adequacy of transjugular liver biopsy (TJLB) specimens with use of the 18-gauge Quick-Core and Flexcore needles. MATERIALS AND METHODS: The records of 233 patients who underwent a TJLB procedure from January 2005 to December 2006 were retrospectively reviewed. Tissue samples from a total of 194 procedures were available for review; 117 TJLB procedures were performed with a Quick-Core needle and 77 were performed with a Flexcore needle. A single pathologist reviewed all the liver biopsy specimens in a blinded fashion. The χ(2), Fisher exact, and Student t tests were used to analyze differences between groups. RESULTS: The TJLB procedure was technically successful in 232 of 233 cases (99.6%). Histologic diagnosis was possible in 96% of cases. Sample fragmentation rates were 24.9% with the Quick-Core needle and 14.3% with the Flexcore needle (P = .1). The mean numbers of complete portal tracts (CPTs) per submitted tissue per procedure were 10.0 ± 4.6 for the Quick-Core needle and 12.2 ± 6.1 for the Flexcore needle (P = .003). The mean numbers of CPTs per liver sample were 2.63 ± 1.8 for the Quick-Core needle and 3.28 ± 3.3 for the Flexcore needle (P = .00004). Complications were more common in patients with multiple comorbidities such as renal failure and coagulopathy and those who had received a liver transplant. CONCLUSIONS: This study demonstrates that the 18-gauge Flexcore TJLB system provided better liver biopsy specimens compared with the 18-gauge Quick-Core needle system.

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.

Frequency of peritoneal infections among patients undergoing continuous paracentesis with an indwelling catheter.

BACKGROUND: Ascites is a common clinical manifestation of advanced liver disease which can be managed with repeated large volume paracentesis. We sought to determine if continuous paracentesis via placement of an indwelling catheter for the management of ascites is safe and effective. METHODS: We placed 38 peritoneal drainage catheters in 30 patients for durations ranging from 1-10 days. Patients underwent ascites fluid culture and cell count determinations immediately before and after the completion of paracentesis. Serum WBC count, BUN and creatinine levels were available on all patients before and after paracentesis. The descriptive data were analysed to assess the rate of peritoneal infections, change in renal function and ultimate clinical outcome of patients. RESULTS: A mean 12.73 litres of peritoneal fluid was removed via continuous peritoneal drainage accomplished with the use of an indwelling abdominal catheter. Eight peritoneal cultures obtained after paracentesis grew out. The mean peritoneal cell count before and after paracentesis in each subject did not show evidence for spontaneous bacterial peritonitis. Five patients underwent successful liver transplantation (OLTX) and did not develop any peritoneal infections post OLTX. CONCLUSION: Continuous large volume paracentesis using an indwelling abdominal catheter for several days is effective in removing large volumes of peritoneal fluid in patients with endstage-liver-disease (ESLD). The peritoneal fluid can grow out bacteria if it is left in the abdomen for > or = 3 days.

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).

Luminescence experiments involved in the mechanism of streptozotocin diabetes and cataract formation.

Streptozotocin (STZ)-induced diabetes is linked to excessive nitric oxide (NO), and possibly peroxynitrite (OONO(-)) and/or other nitrogen oxides, e.g. nitrogen trioxide (N(2)O(3)), which damages DNA of pancreatic beta cells, causing death and loss of insulin. Simultaneous injection of carboxy-PTIO (CPTIO) and STZ prevents diabetes and cataract formation in rats, whereas 4-hydroxy-Tempo (4HT) does not. CPTIO oxidizes nitric oxide to nitrite, which prevents production of the diabetogenic toxin. Peroxynitrite may not be involved, since 4HT (converts O(2)(-) to H(2)O(2)) injected with STZ produces diabetes. All six of the control rats injected with STZ became diabetic and developed cataracts after 3 months. Eight rats injected with STZ and CPTIO were non-diabetic with no cataracts up to a year. This work establishes the idea that excessive nitric oxide is a primary initiator in STZ diabetes. Luminescence experiments using OONO(-) generation from SIN-1 with L-012 indicates that 4HT is an effective inhibitor, while CPTIO is ineffective. Experiments with dilute solutions of nitrogen trioxide added to ladder or plasmid DNA reveal extensive nicking of DNA, thereby raising the possibility that other oxides of nitrogen could be involved with the damage to DNA. It can be concluded that diabetes can be prevented by oxidizing excessive NO from STZ.

Retroperitoneal varices presenting as an adrenal pseudotumor in a cirrhotic patient.

Herein is reported a case of a putative tumor of the left adrenal gland found incidentally during the workup of a cirrhotic patient with portal hypertension. This mass manifested vascular enhancement and other features of an adenoma both on computed tomography (CT) and magnetic resonance imaging (MRI) scans. Additional workup revealed elevated salivary cortisol and plasma aldosterone levels. A proposed biopsy of this mass was deferred because of an episode of variceal bleeding that required placement of a transjugular intrahepatic portosystemic shunt (TIPS). Post TIPS placement, repeat CT and MRI scans showed that the mass had disappeared, indicating that this pseudotumor was, in fact, a knot of peri-adrenal varices, which was now decompressed. In this report, the anatomic and pathologic basis of peri-adrenal varices in a patient with portal hypertension is discussed, as well as the ability of current imaging studies at establishing this diagnosis. Liver disease may cause abnormalities in endocrine function, which make this diagnosis difficult.

Hepatitis C virus: A time for decisions. Who should be treated and when?

Cirrhosis is the most important risk factor for hepatocellular carcinoma (HCC) regardless of the etiology of cirrhosis. Compared to individuals who are anti-hepatitis C virus (HCV) seronegative, anti-HCV seropositive individuals have a greater mortality from both hepatic as well as nonhepatic disease processes. The aim of this paper is do describe the burden of HCV infection and consider treatment strategies to reduce HCV-related morbidity and mortality. The newly developed direct acting antiviral (DAA) therapies are associated with greater rates of drug compliance, fewer adverse effects, and appear not to be limited by the presence of a variety of factors that adversely affect the outcome of interferon-based therapies. Because of the cost of the current DAA, their use has been severely rationed by insurers as well as state and federal agencies to those with advanced fibrotic liver disease (Metavir fibrosis stage F3-F4). The rationale for such rationing is that many of those recognized as having the disease progress slowly over many years and will not develop advanced liver disease manifested as chronic hepatitis C, cirrhosis, and experience any of the multiple complications of liver disease to include HCC. This mitigation has a short sided view of the cost of treatment of hepatitis C related disease processes and ignores the long-term expenses of hepatitis C treatment consisting of the cost of treatment of hepatitis C, the management of cirrhosis with or without decompensation as well as the cost of treatment of HCC and liver transplantation. We believe that treatment should include all HCV infected patients including those with stage F0-F2 fibrosis with or without evidence of coexisting liver disease. Specifically, interferon (IFN)-free regimens with the current effective DAAs without liver staging requirements and including those without evidence of hepatic diseases but having recognized extrahepatic manifestations of HCV infection is projected to be the most cost-effective approach for treating HCV in all of its varied presentations. Early rather than later therapy of HCV infected individuals would be even more efficacious than waiting particularly if it includes all cases from F0-F4 hepatic disease. Timely therapy will reduce the number of individuals developing advanced liver disease, reduce the cost of treating these cases and more importantly, reduce the lifetime cost of treatment of those with any form of HCV related disease as well as HCV associated all - cause mortality. Importantly, HCV treatment regimens without any restrictions would result in a substantial reduction in health care expenditure and simultaneously reduce the number of infected individuals who are infecting others.

Post-transplant IVC occlusion and thrombosis treated with tPA, heparin, and sharp recanalization.

Complete inferior vena cava (IVC) thrombosis can be a lethal complication in a liver transplant recipient. The case of a 52-year-old liver transplant recipient, who developed complete IVC as well as left iliofemoral thrombosis, is reported. After treatment with combined tissue plasminogen activator (tPA) and heparin, the IVC was successfully recanalized with sharp dissection, balloon dilatation, and stent placement.

Postoperative infections in cirrhotic patients.

An overview of the impairments of immune function present and the type as well as frequency of infections seen in individuals with advanced liver disease is presented. Where data are available, the use of antibiotic prophylaxis to prevent these complications is identified. Physicians and surgeons caring for individuals with advanced liver disease need to be aware of these issues and be vigilant to the recognition, early detection and aggressive treatment of infections in patients with advanced liver disease and particularly cirrhosis of any etiology.

Hepatic estrogen receptors and alcohol intake.

Human liver contains estrogen receptors (ER) which render it sensitive to estrogen. Chronic ethanol ingestion in humans and rats results in alterations of circulating sex steroid levels and expression of sex hormone-dependent phenotype. The analysis and quantitation of hepatic estrogen receptor (ER) activity and sex hormone-responsive proteins have been performed over the past two decades. Alcohol abuse appears to induce an increase in ER content of human liver, especially in patients with alcoholic hepatitis actively drinking. This observation is reproduced in an experimental model of chronic alcohol feeding of rats. In male rat liver, the increased ER expression induced by alcohol is associated with an elevated proliferation rate of the hepatocytes. In female liver, the ER content is not affected by alcohol intake and apoptosis prevails over proliferation. The feminization of the liver in males may protect the liver from the severe alcohol-induced liver injury seen in females.

Pericardiocentesis and pancreatic aspiration needle biopsy in coagulopathic and thrombocytopenic cirrhotic patient.

We report on the case of a 40-year-old patient with coagulopathic alcoholic cirrhosis who underwent ultrasound-directed pericardiocentesis and fine-needle aspiration biopsy of the pancreas after receiving recombinant human factor VIIa (rhFVIIa). The infusion of rhFVIIa rapidly corrected her coagulopathy and made it possible to perform both procedures. The marked changes produced in the prothrombin time and international normalized ratio as a result of the infusion of rhFVIIa are presented. As a result of these changes in coagulation status, both procedures were performed safely, and the patient's clinical management and subsequent care plan were defined.

Nonalcoholic fatty liver disease: pathogenesis and the role of antioxidants.

Nonalcoholic fatty liver disease (NAFLD) includes a wide spectrum of liver injury ranging from simple steatosis to steatohepatitis, fibrosis, and cirrhosis. Whereas simple steatosis has a benign clinical course, steatohepatitis is a recognized cause of progressive liver fibrosis and can develop into cirrhosis. NAFLD and nonalcoholic steatohepatitis (NASH) are the two most common chronic liver diseases in United States general population with a prevalence of 20% and 3%, respectively. Hepatic steatosis is frequently associated with obesity, type 2 diabetes, and hyperlipidemia with insulin resistance as a key pathogenic factor. A two-hit theory best describes the progression from simple steatosis to NASH, fibrosis, or cirrhosis. These two hits consist of the accumulation of excessive hepatic fat primarily owing to insulin resistance, and oxidative stress owing to reactive oxygen species (ROS). Mitochondria are the major cellular source of ROS in cases of NASH. Currently, treatment is focused on modifying risk factors such as obesity, diabetes mellitus, and hyperlipidemia. Antioxidants such as vitamin E, N-acetylcysteine, betaine, and others may be beneficial in the treatment of NASH.