Mild hyperbilirubinemia as a marker of oesophageal varices in HCV-related compensated cirrhotic patients.

The natural course of compensated liver cirrhosis caused by chronic hepatitis C virus (HCV) infection is still a very interesting problem in hepatology. The prognostic usefulness of the Child-Pugh and MELD score in compensated liver cirrhosis is still debated. Consequently, several attempts have been made to determine parameters other than included in the Child-Pugh score, which could be helpful in the prognosis of compensated liver cirrhosis assessment. AIM: The aim of study was to identify a clinical or laboratory markers correlated with higher risk of liver decompensation among HCVinfected patients with compensated liver cirrhosis and presence or absence of esophageal varices. MATERIALS AND METHODS: The study included 176 HCV-infected patients with compensated liver cirrhosis (74 women and 102 men) registered in the Clinical Database of Patients with Liver Cirrhosis - e-Hepar. All patients were monitored during 252 weeks for the occurrence of liver failure symptoms and the development of hepatocellular carcinoma (HCC). RESULTS: The presence of esophageal varices was significantly associated with total bilirubin ≥2.0 mg/dl, platelets ≤110.0 G/L and 6 points in Child-Pugh score (p<0.05). The cumulative 252 weeks incidence of clinical decompensation was higher in patients with varices in comparison to patients without them (p<0.05). Variceal hemorrhages were observed in 9 cases (23.1%). During the follow-up period 9 patients died due to HCC complications. CONCLUSIONS: Our findings underline the prognostic value of serum bilirubin (even mild elevation) and platelet count in HCV-infected patients with compensated liver cirrhosis. We have confirmed that liver decompensation is more frequent and more rapid in patients with compensated liver disease and concomitant oesophageal varices.

Albinterferon Alfa-2b was not inferior to pegylated interferon-α in a randomized trial of patients with chronic hepatitis C virus genotype 1.

BACKGROUND & AIMS: The current standard of care for patients with chronic hepatitis C virus (HCV) genotype 1 is once-weekly pegylated interferon-α (Peg-IFNα) plus daily ribavirin for 48 weeks. We evaluated the efficacy/safety of albinterferon alfa-2b (albIFN), a novel, long-acting, genetic fusion polypeptide of albumin and IFNα-2b. METHODS: In the phase 3 ACHIEVE-1 trial, 1331 patients were assigned equally to 3 open-label, 48-week treatment groups: Peg-IFNα-2a 180 µg every week, or albIFN 900 or 1200 µg every 2 weeks administered subcutaneously, with weight-based oral ribavirin 1000-1200 mg/day. During the study, the data monitoring committee recommended dose modification for all patients receiving albIFN 1200 µg to 900 µg because of increased pulmonary adverse events (AEs) in the 1200-µg arms of both ACHIEVE studies. Main outcome measure was sustained virologic response (SVR; undetectable serum HCV RNA at week 72). RESULTS: Intention-to-treat SVR rates were 51.0% (225/441), 48.2% (213/442), and 47.3% (208/440) with Peg-IFNα-2a, and albIFN 900 and 1200 µg, respectively. The primary objective of showing noninferiority of albIFN 900 µg (P < .001) and 1200 µg (P = .003) vs Peg-IFNα-2a for SVR was achieved. Multivariate modeling indicated consistency of treatment effect across subgroups. Serious/severe AE rates were 23.1%, 24.0%, 28.2%; treatment discontinuation rates because of AEs were 4.1%, 10.4%, 10.0%; discontinuation rates because of respiratory AEs were 0%, 0.9%, 1.6%; with Peg-IFNα-2a, and albIFN 900 and 1200 µg, respectively. Hematologic abnormality rates were comparable across the Peg-IFNα-2a and albIFN 900-µg groups. CONCLUSIONS: albIFN 900 µg every 2 weeks showed comparable efficacy, with similar serious/severe AE rates, although with a higher discontinuation rate, vs Peg-IFNα-2a in patients with chronic HCV genotype 1.

[Physiological functions of L-ornithine and L-aspartate in the body and the efficacy of administration of L-ornithine-L-aspartate in conditions of relative deficiency]. / Fizjologiczne funkcje L-ornityny i L-asparaginianu oraz celowosc podawania asparaginianu ornityny w stanach wzglednego niedoboru.

L-ornithine-L-aspartate (LOLA) is a stable salt of two natural nonessential L-amino acids: ornithine and aspartic acid. It is formulated and marketed in low and high doses. Low doses are used as a food supplement and high doses (above 5 g) as a medicinal product to lower blood ammonia concentration and to eliminate symptoms of hepatic encephalopathy associated with liver cirrhosis. The aim of this review is to present physiological roles of L-ornithine and L-aspartate in the human body, to assess conditions under which these amino acids could be deficient, to analyze consequences of these deficiencies, and to review the current state of knowledge on the effects of LOLA administration. The data used in this publication result from searches of different electronic databases such as Cochrane Trials Register, MEDLINE, PubMed, Medscape, or Google Scholar, with a cut-off date of November 29, 2009, using terms: L-ornithine-L-aspartate, ornithine aspartate, ornithine, Hepa-Merz, ornithine deficiency, hyperammonemia, hepatic encephalopathy, and liver cirrhosis. Both amino acids play key roles in ammonia detoxification and in proline and polyamine biosyntheses. Polyamines are considered critical for DNA synthesis and cell replication and have been shown to stimulate hepatic regeneration. Supplementation with ornithine in animal models demonstrated enhanced wound breaking strength and collagen deposition. It has been shown in vitro, in vivo and in perfused organs that urea synthesis from ammonia is limited by endogenous ornithine and that ornithine can pharmacologically promote urea formation to a greater degree than any ammonia supply. Administration of LOLA in high doses reduced high blood ammonia induced either by ammonium chloride or protein ingestion or existing as a clinical complication of cirrhosis. In health and with proper diet, L-ornithine and L-aspartate are synthesized de novo in sufficient quantities, but in the states of disease, tissue damage, organ insufficiency, excessive metabolic demand, growth, pregnancy, or urea cycle enzyme deficiencies, these amino acids need to be supplemented with the food. The review of available data indicate that there is direct and indirect (resulting from physiology) scientific rationale for dietary use of LOLA, depending on an individual's physiological, metabolic or pathological conditions. In conditional ornithine deficiency, daily supplementation with LOLA at doses about 1 g/day is safe and, as demonstrated in vitro, should be sufficient to saturate tissue ornithine concentration to prevent postprandial hyperammonemia and to stimulate tissue regeneration.

[Antiviral treatment of chronic B hepatitis; 2010 - therapeutic recommendations]. / Leczenie przeciwwirusowe przewleklego zapalenia watroby typu B--zalecenia terapeutyczne 2010.

The drugs currently approved for treatment of HBV infections are: interferon alpha2a and alpha2b, pegylated interferon (PeglFN-al-pha2a) natural interferons and nucleos(t)ide analogues (NA): adefovir, entecavir, lamivudine, telbivudine (currently not available in Poland) and tenofovir. The following questions are described: the primary goal of antiviral treatment, criteria in therapeutic decision-making (including extrahepatic manifestations, compensated and decompensated cirrhosis of the liver), treatment failure (including: drug resistance), management of patients with HBV-positive markers, in whom chemotherapy or other immunosuppressive therapy is planned. In treatment-naive patients with chronic hepatitis B the first line therapy should be PeglFN-alpha2a monotherapy, and the first-line should be entecavir or tenofovir (highest potential for HBV replication suppression and high genetic barrier to resistance). In drug resistance the patient should be switched to another, preferably high-potency NA (entecavir or tenofovir) or start PeglFN-alpha2a therapy.

[Seroprevalence of anti-HCV in pregnant women. Risk factors of HCV infection]. / Czestosc wystepowania przeciwcial anty-HCV u kobiet ciezarnych. Analiza czynników ryzyka zakazenia HCV.

UNLABELLED: Vertical transmission seems to be an important mode of infection in children. Approximately 6-9% of hepatitis C virus-positive women transmit HCV to their offsprings. AIM: 1. To determine the frequency of HCV infection in pregnant women in central Poland. 2. To estimate knowledge about HCV infection in childbearing women. 3. To identify risk factors for HCV infection among pregnant women. METHODS: Study in two separate parts. Part A: Blood samples were collected from 544 pregnant women, tested with anti-HCV ELISA third generation tests. Part B: Data of risk factors of HCV infection, reason of diagnostics were assessed through structured interview and review of available medical records in 281 women infected with HCV. RESULTS: Part A: 2.02% of tested pregnant women were anti-HCV(+). One of them (1/11) knew about her HCV infection before examination. Part B. 24% of 281 infected women indicate a history of blood products transfusion (all before 1992), 23%- hospitalisation with surgical procedures, 15%--intravenous drug use, 8%--hospitalisation without surgical procedures, 7%--exposures of health care personnel, 3%--infected mother, 3%--sexual partner or other member of family infected with HCV. Histories taken from 17% women did not include any known risk factors. HCV infection in women were diagnosed: before pregnancy in 186 (66%), during pregnancy in 61 (22%), after delivery in 34 (12%). All women were Caucasian, Polish nationality. CONCLUSION: The seroprevalence of anti-HCV in pregnant women was 2.02%. There is a number of childbearing HCV infected women who are not identified as HCV positive. Selective HCV testing to women at high risk of HCV infection and antiviral therapy should be encouraged prior to conception.

[Mother-to-infant HCV transmission--rate and course of HCV infection in children]. / Zakazenie wertykalne HCV--ocena czestosci i przebiegu zakazenia u dzieci.

OBJECT: to establish the rate and course of HCV infection in infants born to HCV infected mothers and to determine abilities of prevention. METHODS: 155 children born to HCV infected mothers were observed from birth until age 18-48 months. Serum of infants was tested for HCV-RNA (RT-PCR, Amplicor v 2.0 Roche), for anti-HCV (EIA v. 2) and ALT activity. Infants were classified as HCV infected if their serum was found to be positive for HCV-RNA at least twice during first year of life. In 11 mothers and their newborns serum and PBMC from venous blood and from the umbilical cord were collected during delivery and examined-using nested RT-PCR. RESULTS: The overall HCV vertical infection rate was 11%. Transmission occurred more frequently in children with intrapartum exposure to maternal blood by percutaneus inoculation. None of the infected infants had clinical symptoms of hepatitis. ALT abnormal activity was detected in 43% of infected children. HCV-RNA was detected in mothers' serum and PBMC collected during delivery in 9 (9/11) samples. HCV-RNA was detected in samples from umbilical cord in serum in 7 (7/11) and in PBMC in 4 (4/11) cases. CONCLUSIONS: The risk of HCV vertical infection in present study was high. Intrapartum percutaneus exposure to maternal blood increased transmission rates. Further investigation to determine the effectiveness of antiviral therapy in prevention of mother-to-infant HCV transmission should be performed. The role of PBMC in mother-to-child HCV transmission should be investigated.

Pigment epithelium-derived factor and matrix metalloproteinase-9 in liver cirrhosis.

BACKGROUND/AIM: The aim of this study was to assess the role of serum pigment epithelium-derived factor (PEDF) and matrix metalloproteinase-9 (MMP-9) in progression of liver cirrhosis and development of hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Serum levels of PEDF and MMP-9 were tested in 212 patients with liver cirrhosis and in a control group of 30 healthy volunteers. HCC was diagnosed in 45 of the 212 patients studied (21%). RESULTS: Serum PEDF and MMP-9 were higher in the study group than that in the control group (P < 0.001). In patients with alcoholic or mixed (alcoholic and viral hepatitis-related) cirrhosis, serum PEDF was higher than that in other patients (13970.2 ± 13406.9 ng/ml vs. 8563.5 ± 9602.7 ng/ml, P = 0.008). In patients with viral hepatitis-related cirrhosis, significantly higher PEDF levels were recorded in those with HCC (13429.1 ± 12045.8) than that in patients without HCC (6660.1 ± 7927.1; P = 0.04). There was a trend for higher serum MMP-9 in patients with HCC (5778.7 ± 12426.6 vs. 1389.8 ± 1944.7 in those without HCC; P = 0.07). Significant negative correlation between serum MMP-9 and serum alpha-fetoprotein in patients with HCC was observed (r = -0.54; P = 0.04). CONCLUSION: Serum PEDF and MMP-9 could be auxiliary markers in diagnosis of HCC, especially in patients with low alpha-fetoprotein level. Alcohol consumption can affect serum PEDF.

[Epidemic outbreak of acute hepatitis C--clinical course, histology and effectiveness of therapy]. / Ognisko ostrego wirusowego zapalenia watroby typu C--przebieg kliniczny, obraz histopatologiczny i skutecznosc terapii.

An epidemic outbreak of HCV infection was observed in the center of nonconventional therapy, when patients with stable coronary heart disease and arteriosclerosis obliterans were treated. They received drop infusions with chelate therapy with unknown medicine. We diagnosed acute hepatitis C in 15 patients (mean age 61). All were positive for HCV RNA, had known exposure to HCV within the preceding 3 months and elevated serum ALT value 2-10 ULN. 12 out of 15 patients had documented seroconversion to anti-HCV. In 6 patients liver biopsy was performed. Acute viral hepatitis was diagnosed in 4 cases (of mild activity in 2 cases and of moderate activity in the other two cases). In two remaining cases histology required differentiation diagnosis (one with non alcoholic steatohepatitis and one with exacerbation of chronic hepatitis). Different forms of hepatocyte degeneration and steatosis were observed in all cases. Considering the possibility to chronicity we decided to treat 10 patients, while remaining 5 had contraindications to interferon therapy. There was no control group. Patients were treated with pegylated alfa 2b interferon 1.5 mcg/kg/week and ribavirin 1000-1200 mg/d, for 12 weeks. Side effects appear minimal. In no case therapy was interrupted. Sustained viral response (SVR) and normalization of ALT were observed in 6 out of 10 treated patients (1 with jaundice and 5 asymptomatic). Two untreated subjects had spontaneous recovery. We found that administration of pegylated interferon alfa-2b and ribavirin 1-6 months after the appearance of jaundice or significant elevation of ALT activity could prevent progression to chronic infection. This therapy appears to be effective and safe in asymptomatic infection and among others in adult patients with stable coronary heart disease. Our results confirmed the previous observations mentioned by others that treatment of acute hepatitis C with pegylated interferon and ribavirin may lead to cure.

[Pegylated interferon-alfa 2a with ribavirin in chronic viral hepatitis C (final report)]. / Pegylowany interferon alpha-2a z rybawiryna w leczeniu przewleklego wirusowego zapalenia watroby typu C (raport koncowy z badan).

UNLABELLED: We evaluated the efficacy and safety of peginterferon alfa-2a [40KD] (Peg-IFNalpha-2a) plus ribavirin in patients with chronic hepatitis C in an open-label programme in a routine clinical setting in Poland. Patients received Peg-IFNalpha-2a 180mg/week plus ribavirin 800-1200 mg/d for 48 weeks. Sustained virological response (SVR) was defined as undetectable HCV RNA (<50IU/mL) at the end of follow-up (week 72). 466 adults were enrolled. Most patients (87.3%) had genotype 1 infection. 440 subjects (94,4%) completed treatment. The overall SVR rate was 55.7%. A higher SVR rate was obtained in treatment-naïve patients (58.7%) than in relapsers (47.8%; p=0,048). SVR rates in genotype 1 and non-1 patients were 51.1% and 88.5%, respectively (p<0.001). There were significant higher SVR rates in patients with lower baseline fibrosis (p=0,01). There were no differences in SVRs by gender or viral load. Hemoglobin, leukocyte and neutrophil levels decreased significantly during treatment, but returned to baseline after the end of treatment. ALT levels decreased significantly during treatment in patients with and without an SVR. 38.4% of patients experienced adverse events like neutropenia, anemia, thrombocytopenia, and other. There was one death (severe thrombocytopenia). CONCLUSIONS: The overall SVR achieved in this predominantly genotype 1 population was 55.7%. SVR rates were significantly higher in treatment-naïve patients, those with non-1 genotypes, and in patients with lower baseline fibrosis scores.

[HGV, TTV and SEN viruses--are these organisms pathogenic?]. / Wirusy GBV, TTV, SEN--kontrowersje wokól ich patogennosci.

After the discovery of hepatitis A, B, C, D and E viruses, several lines of evidence suggested that an additional hepatitis agent (s) might exist. Molecular approaches led sequentially to the discoveries of GBV-C/HGV, TTV and more recently SENV. At issue is whether these agents cause non - A non - E hepatitis and/or some extrahepatic diseases. These problems are discussed in present paper, considering the newest data from literature.

[Analysis of HBV source in patients hospitalized at the Department of Hematology and Clinical Immunology of the Medical Academy in Warsaw in the years 2000-2003]. / Analiza zródel zakazenia HBV u pacjetów Kliniki Hepatologii i Nabytych Niedoborów Immunologicznych Akademii Medycznej w Warszawie w latach 2000--2003.

The purpose of the study was to evaluate routes of HBV transmission in 140 patients hospitalized in the Department of Hepatology and AIDS, Medical University of Warsaw in the years 2000--2003. Authors found two major routes of HBV infection in the observed patients: drug abuse and the unknown route in the group of young people and infection transmitted at the non-surgical wards among the patients older than 40 years.

Is there any influence of immune deficit on procalcitonin results?

The role of procalcitonin (PCT) in immunocompromised patients is still under investigation. This study evaluated the influence of immune deficiency on the value of PCT concentrations in the diagnosis of early stages of bacterial infections in human immunodeficiency virus (HIV)-infected patients compared with other inflammatory markers, such as C-reactive protein and white blood cell count. We analyzed major immunologic markers including CD4, CD8, and HIV-1 viral load. PCT concentrations in the early stages of bacterial infections correlated negatively with CD4 count in HIV-infected patients. However, a similar relation was not seen in patients with acquired immune deficiency syndrome. We support the recommendation to change the cutoff value ranges of PCT in patients with immune deficiency. PCT concentrations can be influenced by various factors and hence should be carefully analyzed, especially in immunocompromised patients.

Present and future possibilities for early diagnosis of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) represents the fifth most common cancer in the world, and the third most frequent oncological cause of death. The incidence of HCC is on the increase. HCC typically develops in patients with chronic liver diseases, and cirrhosis, usually with viral etiology, is the strongest predisposing factor. Nowadays HCC diagnosis is a multistage process including clinical, laboratory, imaging and pathological examinations. The prognosis of HCC is mostly poor, because of detection at an advanced, non-resectable stage. Potentially curative treatment (surgery) is limited and really possible only for cases with small HCC malignancies. For this reason, more effective surveillance strategies should be used to screen for early occurrence of HCC targeted to the population at risk. So far, the generally accepted serological marker is alpha-fetoprotein (AFP). Its diagnostic accuracy is unsatisfactory and questionable because of low sensitivity, therefore there is a strong demand by clinicians for new HCC-specific biomarkers. In this review, we will focus on other biomarkers that seem to improve HCC diagnosis, such as AFP-L3, des-gamma-carboxyprothrombin, alpha-l-fucosidase, gamma-glutamyl transferase, glypican-3, squamous cell carcinoma antigen, a new generation of immunoglobulin M-immunocomplexes, and very promising gene-expression profiling.

Efficacy of 24 weeks treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C infected with genotype 1 and low pretreatment viremia.

BACKGROUND/AIMS: Previous studies using standard interferon and ribavirin combination therapy suggested that patients infected with HCV-1 and a low pretreatment HCV-RNA level can be treated for 24 weeks without compromising sustained virologic response rates. The aim of the present study was to investigate this schedule in the era of pegylated interferon-alpha plus ribavirin. METHODS: Patients chronically infected with HCV-1 (n=235) and a screening viremia < or =600,000 IU/mL (real-time PCR) were treated with peginterferon alfa-2b 1.5 microg/kg subcutaneously once weekly plus ribavirin 800-1400 mg/day based on body weight for 24 weeks. RESULTS: End-of-treatment and sustained virologic response rates were 80 and 50%, respectively. The 48-week historical control (Manns et al., Lancet 2001;358:958-65) had similar end-of-treatment (74%) but higher sustained virologic response rates (71%). This difference was due to a high virologic relapse rate after 24 weeks of therapy (37%) compared with the historical control (4%). A subset of patients who had undetectable serum HCV-RNA at treatment week 4, however, achieved similar sustained virologic response rate (89%) as in the control group (85%). CONCLUSIONS: HCV-1 infected patients with a low baseline HCV-RNA concentration who become HCV-RNA negative at week 4 may be treated for 24 weeks without compromising sustained virologic response rates.

Entecavir for treatment of lamivudine-refractory, HBeAg-positive chronic hepatitis B.

BACKGROUND & AIMS: Lamivudine treatment is associated with frequent development of resistant hepatitis B virus (HBV) and loss of treatment benefit. In preclinical and phase II studies, entecavir demonstrated potent antiviral activity against lamivudine-resistant HBV. METHODS: In this phase III, double-blind trial, hepatitis B e antigen-positive patients who were refractory to lamivudine therapy (persistent viremia or documented YMDD mutations while receiving lamivudine) were randomized to switch to entecavir 1 mg daily (n = 141) or continue lamivudine 100 mg daily (n = 145) for a minimum of 52 weeks. Two coprimary end points were assessed at 48 weeks: histologic improvement and a composite end point (HBV branched DNA <0.7 MEq/mL and alanine aminotransferase [ALT] <1.25 times the upper limit of normal). RESULTS: Histologic improvement occurred in 55% (68/124) of entecavir-treated vs 28% (32/116) of lamivudine-treated patients (P < .0001). More patients on entecavir than lamivudine achieved the composite end point: 55% (77/141) vs 4% (6/145), respectively (P < .0001). Mean change from baseline in HBV DNA was -5.11 log(10) copies/mL for entecavir-treated patients and -0.48 log(10) copies/mL for lamivudine-treated patients (P < .0001). Virologic rebound because of entecavir resistance substitutions occurred in 2 of 141 of entecavir-treated patients, and genotypic evidence of resistance was detected in 10 patients. The safety profile of entecavir was comparable to lamivudine with fewer ALT flares on treatment. CONCLUSIONS: In patients with lamivudine-refractory chronic hepatitis B, switching to entecavir provides superior histologic improvement, viral load reduction, and ALT normalization compared with continuing lamivudine, with a comparable adverse event profile.