BACKGROUND & AIMS: Eight-week glecaprevir/pibrentasvir leads to high rates of sustained virological response at post-treatment week 12 (SVR12) across HCV genotypes (GT) 1-6 in treatment-naïve patients without cirrhosis. We evaluated glecaprevir/pibrentasvir once daily for 8 weeks in treatment-naïve patients with compensated cirrhosis. METHODS: EXPEDITION-8 was a single-arm, multicenter, phase IIIb trial. The primary and key secondary efficacy analyses were to compare the lower bound of the 95% CI of the SVR12 rate in i) patients with GT1,2,4-6 in the per protocol (PP) population, ii) patients with GT1,2,4-6 in the intention-to-treat (ITT) population, iii) patients with GT1-6 in the PP population, and iv) patients with GT1-6 in the ITT population, to pre-defined efficacy thresholds based on historical SVR12 rates for 12 weeks of glecaprevir/pibrentasvir in the same populations. Safety was also assessed. RESULTS: A total of 343 patients were enrolled. Most patients were male (63%), white (83%), and had GT1 (67%). The SVR12 rate in patients with GT1-6 was 99.7% (n/N = 334/335; 95%CI 98.3-99.9) in the PP population and 97.7% (n/N = 335/343; 95% CI 96.1-99.3) in the ITT population. All primary and key secondary efficacy analyses were achieved. One patient (GT3a) experienced relapse (0.3%) at post-treatment week 4. Common adverse events (≥5%) were fatigue (9%), pruritus (8%), headache (8%), and nausea (6%). Serious adverse events (none related) occurred in 2% of patients. No adverse event led to study drug discontinuation. Clinically significant laboratory abnormalities were infrequent. CONCLUSIONS: Eight-week glecaprevir/pibrentasvir was well tolerated and led to a similarly high SVR12 rate as the 12-week regimen in treatment-naïve patients with chronic HCV GT1-6 infection and compensated cirrhosis. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03089944. LAY SUMMARY: This study was the first to evaluate an 8-week direct-acting antiviral (DAA) regimen active against all major types of hepatitis C virus (HCV) in untreated patients with compensated cirrhosis. High virological cure rates were achieved with glecaprevir/pibrentasvir across HCV genotypes 1-6, and these high cure rates did not depend on any patient or viral characteristics present before treatment. This may simplify care and allow non-specialist healthcare professionals to treat these patients, contributing to global efforts to eliminate HCV.

• Klíčová slova
• Chronic HCV infection, Compensated cirrhosis, Direct-acting antiviral, Glecaprevir/pibrentasvir, HCV elimination, Hepatitis C virus, Pangenotypic, Short duration,
• MeSH
• antivirové látky aplikace a dávkování   škodlivé účinky   MeSH
• benzimidazoly aplikace a dávkování   škodlivé účinky   MeSH
• chinoxaliny aplikace a dávkování   škodlivé účinky   MeSH
• chronická hepatitida C krev   komplikace   farmakoterapie   virologie   MeSH
• cyklopropany aplikace a dávkování   škodlivé účinky   MeSH
• fixní kombinace léků MeSH
• genotyp * MeSH
• Hepacivirus enzymologie   genetika   MeSH
• jaterní cirhóza komplikace   farmakoterapie   MeSH
• kyseliny aminoisomáselné aplikace a dávkování   škodlivé účinky   MeSH
• leucin aplikace a dávkování   škodlivé účinky   analogy a deriváty   MeSH
• lidé středního věku MeSH
• lidé MeSH
• makrocyklické laktamy aplikace a dávkování   škodlivé účinky   MeSH
• polymorfismus genetický MeSH
• prolin aplikace a dávkování   škodlivé účinky   analogy a deriváty   MeSH
• pyrrolidiny aplikace a dávkování   škodlivé účinky   MeSH
• RNA virová krev   genetika   MeSH
• senioři MeSH
• setrvalá virologická odpověď MeSH
• sulfonamidy aplikace a dávkování   škodlivé účinky   MeSH
• virové nestrukturální proteiny genetika   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antivirové látky MeSH
• benzimidazoly MeSH
• chinoxaliny MeSH
• cyklopropany MeSH
• fixní kombinace léků MeSH
• glecaprevir MeSH Prohlížeč
• kyseliny aminoisomáselné MeSH
• leucin MeSH
• makrocyklické laktamy MeSH
• NS-5 protein, hepatitis C virus MeSH Prohlížeč
• NS3 protein, hepatitis C virus MeSH Prohlížeč
• pibrentasvir MeSH Prohlížeč
• prolin MeSH
• pyrrolidiny MeSH
• RNA virová MeSH
• sulfonamidy MeSH
• virové nestrukturální proteiny MeSH

BACKGROUND: Cholesterol is derived via de novo synthesis and dietary absorption. Both processes can be monitored by determination of non-cholesterol sterol concentrations (lathosterol for synthesis; sitosterol and campesterol for absorption). The hypocholesterolemia that occurs during acute illness is a result of a multifactorial inability to compensate for the increased needs for this metabolite. The aim of this study was to examine the plasma cholesterol profile and both processes of cholesterol acquisition during acute upper gastrointestinal haemorrhage with emphasis on liver cirrhosis. MATERIAL AND METHODS: Thirty five patients with acute upper gastrointestinal bleeding (cirrhosis n=14, non-cirrhosis n=21) were evaluated over a 6 day period. The control cohort consisted of 100 blood donors. Serum concentrations of total, LDL (low-density lipoprotein) and HDL (high-density lipoprotein) cholesterol were measured enzymatically. Sterol concentrations were analysed using gas chromatography, data were statistically analysed. RESULTS: In all patients, we found lower plasma levels of total cholesterol (P Conclusion: Our results showed substantial abnormalities in the cholesterol plasma profile including both the processes of cholesterol acquisition in patients with upper acute gastrointestinal bleeding. The patients with or without liver cirrhosis had similar trends in cholesterol plasma levels. Depression of cholesterol synthesis was, however, prolonged in the cirrhotic group and the data also suggest a different phytosterol metabolism.

• Klíčová slova
• acute gastrointestinal bleeding, cholesterol, hypocholesterolemia, lipids, liver cirrhosis, non-cholesterol sterols, phytosterols,
• MeSH
• akutní nemoc MeSH
• cholesterol metabolismus   MeSH
• dyslipidemie krev   etiologie   MeSH
• fytosteroly metabolismus   MeSH
• gastrointestinální krvácení krev   MeSH
• HDL-cholesterol metabolismus   MeSH
• jaterní cirhóza krev   MeSH
• LDL-cholesterol metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• studie případů a kontrol MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• cholesterol MeSH
• fytosteroly MeSH
• HDL-cholesterol MeSH
• LDL-cholesterol MeSH

Trimecaine (Mesocain, Léciva) an analogous preparation to lidocaine is used as a local anaesthetic, antiarrhythmic and spasmolytic preparation. The purpose of the investigation was to assess the fate of trimecaine in nine patients with compensated cirrhosis of the liver. The pharmacokinetics were evaluated after intravenous infusion of trimecaine administered at a rate of 150-200 mg.h-1. Plasma concentrations of the drug evaluated by gas chromatography indicate a marked retardation of trimecaine elimination in patients with liver damage. In the group of patients with cirrhosis of the liver the total clearance of the drug was lower (8.7 +/- 5.0 1.h-1), as compared with the group of patients without liver damage (34.7 +/- 19.4 1.h-1). In patients with cirrhosis of the liver also a multiple reduction of distribution volumes was observed. The results indicate a high hepatic extraction of

• MeSH
• jaterní cirhóza metabolismus   MeSH
• lidé MeSH
• trimekain farmakokinetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• Názvy látek
• trimekain MeSH

BACKGROUND & AIMS: Patients with decompensated cirrhosis suffer from recurrent infections and inadequate responses to prophylactic vaccinations. However, many patients present with hypergammaglobulinemia (HGG), indicating a sustained ability to generate antibody responses. As follicular T helper (Tfh) cells are central facilitators of humoral immunity, we hypothesized that Tfh cell responses may be altered in advanced liver disease and we aimed to identify the mechanisms underlying any such alterations. METHODS: Tfh, regulatory T (Treg) cells, B cells, circulating cytokines and immunoglobulins were analyzed in cohorts of patients with compensated (n = 37) and decompensated cirrhosis (n = 82) and in non-cirrhotic controls (n = 45). Intrahepatic T cells were analyzed in 8 decompensated patients. The influence of IL-2 on Tfh cell function was evaluated in vitro, including Tfh cell cloning and T cell-B cell co-cultures with clones and primary tonsil-derived Tfh cells. RESULTS: Tfh cell frequencies were reduced in patients with decompensated cirrhosis, with phenotypic signatures indicative of increased IL-2 signaling. Soluble IL-2 receptor (sCD25) was elevated in these patients and CD4 T cells were more responsive to IL-2 signaling, as characterized by STAT5 phosphorylation. IL-2 exposure in vitro diminished the Tfh phenotype and resulted in impaired Tfh helper function in co-culture experiments with naïve B cells. Tfh cells were barely detectable in cirrhotic livers. IL-2 signatures on Tfh cells in decompensated patients correlated with immunoglobulin levels, which were found to be associated with improved survival. CONCLUSIONS: Tfh cell impairment represents a previously underestimated feature of cirrhosis-associated immune dysfunction that is driven by IL-2. The presence of HGG in decompensated patients predicts an intact Tfh cell compartment and is associated with a favorable outcome. LAY SUMMARY: Patients with advanced cirrhosis often fail to generate protective immunity after prophylactic vaccinations and suffer from recurring infections that are associated with high mortality. Follicular T helper (Tfh) cells are specialized CD4 T cells that enable the emergence of antibody responses against microbial pathogens. This report demonstrates that Tfh cells are impaired in patients with advanced cirrhosis due to interleukin-2 signaling, a cytokine that is known to impair the generation of Tfh cells.

• Klíčová slova
• CD4 T cells, Cellular immunity, Hepatic decompensation, Immunosuppression,
• MeSH
• B-lymfocyty imunologie   MeSH
• dospělí MeSH
• folikulární pomocné T-buňky imunologie   MeSH
• hypergamaglobulinemie komplikace   MeSH
• imunoglobulin G krev   MeSH
• interleukin-2 krev   MeSH
• jaterní cirhóza krev   komplikace   imunologie   MeSH
• kohortové studie MeSH
• kokultivační techniky MeSH
• kultivované buňky MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorové supresorové proteiny metabolismus   MeSH
• prognóza MeSH
• průřezové studie MeSH
• regulační T-lymfocyty imunologie   MeSH
• senioři MeSH
• signální transdukce imunologie   MeSH
• transkripční faktor STAT5 metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• IL2 protein, human MeSH Prohlížeč
• imunoglobulin G MeSH
• interleukin-2 MeSH
• nádorové supresorové proteiny MeSH
• STAT5A protein, human MeSH Prohlížeč
• transkripční faktor STAT5 MeSH

5 patients with primary biliary cirrhosis (PBC), 9 patients with compensated hepatic cirrhosis of different etiology and 12 control persons were tested for renal acidification after peroral CaCl2 administration and urine Na2SO4 and pCO2 infusion as well as the gradient between partial urine pressure and blood pressure after NaHCO3 application. Distal renal tubular acidosis (DRTA) was diagnosed in one patient with PBC, latent DRTA in other 2 patients with PBC. Not even one patient's acidification disorder was eliminated through an increased sodium application to the acidification site after Na2SO4 application. After NaHCO3 application, the gradient between the CO2 partial pressure in the urine and blood in both patients with PBC was, however, latent, DRTA normal. After pH gradient elimination in patients with PBC and DRTA, the hydrogen iont secretion is thus comparable with the control persons. Based on this study, the authors believe that the gradient type of DRTA is characteristic of primary biliary cirrhosis.

• MeSH
• biliární cirhóza komplikace   MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• renální tubulární acidóza komplikace   metabolismus   terapie   MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH

• MeSH
• dospělí MeSH
• jaterní cirhóza metabolismus   MeSH
• kinetika MeSH
• laktáty metabolismus   MeSH
• lidé MeSH
• pyruváty metabolismus   MeSH
• spotřeba kyslíku MeSH
• tělesná námaha MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• laktáty MeSH
• pyruváty MeSH

UNLABELLED: There are 40 000-60 000 patients with cirrhosis in the Czech Republic. 2 000 die of this disease yearly. This group of patients needs a complex treatment and it is mostly an internist cooperating with other specialists. The most important for an ambulant internist is to diagnose the disease as soon as possible and start with treatment of chronic liver disease that could lead to a cirrhosis. It means especially chronic viral hepatitis, alcoholic or non-alcoholic steatosis/steatohepatitis, auto-immune liver damage and metabolic disease. The next step is to diagnose the cirrhosis in time when it is in no manifest stage. The third step is to diagnose and treat the liver decompensation. It means consequences of the portal hypertension, it is ascit, esophageal or gastric varices, hepatorenal syndrome. Next there are consequences of the metabolic insufficiency, it is icterus, coagulopathy and hepatic encephalopathy. It is necessary to diagnose and cure cholestasis from the very first extrahepatic causes. For a successful treatment of the hepatocellular carcinoma originated almost exclusively in the grounds of the cirrhosis must be early diagnosed. The ambulant internist respective hepatologist must diagnose the stage of the cirrhosis and decide when a hospitalization is necessary. Also a close cooperation with other specialists is urgent if it is about a liver transplantation. The treatment of successive stages of the cirrhosis is a topic of the showed educational article. KEY WORDS: compensated/decompensated liver cirrhosis - diet/nutrition in liver cirrhosis - etiology and diagnose of liver cirrhosis - treatment of liver insufficiency/failure - treatment of portal hypertension and its complications.

• MeSH
• ambulantní péče MeSH
• jaterní cirhóza diagnóza   etiologie   terapie   MeSH
• kurzy a stáže v nemocnici MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Geografické názvy
• Česká republika MeSH

Previous investigations of authors abroad provided evidence of a reduction of portal pressure by blockers of slow calcium channels group II by verapamil. We decided to investigate the effect of a quite new preparation dilthiazem on the portal haemodynamics in patients with compensated cirrhosis of the liver and oesophageal varices. Doppler examinations of the width, rate of blood flow and flow through the trunk of the portal vein did not prove a statistically significant effect of dilthiazem on the investigated parameters. After the preparation a significant decline of the median pressure in the pulmonary artery was recorded at the 5% level of significance. The significantly elevated pressure values in the wedged position in the hepatic vein (WHVP) as well as of the portohepatic gradient (P-H) rose further after administration of the preparation (WHVP by 12.3%, p P-H by 15%). Even maximum doses of dilthiazem did not influence the portal flow in patients and did not lead to a reduction of the portohepatic gradient. From the results it is apparent that dilthiazem is not suitable for the treatment of portal hypertension.

• MeSH
• diltiazem farmakologie   MeSH
• hemodynamika účinky léků   MeSH
• jaterní cirhóza diagnostické zobrazování   patofyziologie   MeSH
• lidé MeSH
• ultrasonografie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• diltiazem MeSH

The authors evaluate more than 12 years of their own experience with the administration of colchicine to patients with cirrhosis of the liver. Colchicine did not produce any apparent undesirable effects. The authors emphasize the absence of knowledge of prognostic parameters (except the stage of the disease and its activity) which would make it possible to evaluate in advance the effect of many years' treatment. They deal separately with a patient who entered their investigation in a very advanced stage of the disease and survived after he had recovered full compensation and did not depend on diuretic treatment.

• MeSH
• dospělí MeSH
• jaterní cirhóza farmakoterapie   MeSH
• kolchicin škodlivé účinky   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• Názvy látek
• kolchicin MeSH

The authors assessed in 12 patients with compensated cirrhosis of the liver, portal hypertension and oesophageal varices, using a Doppler flowmeter Toshiba SAL 50A/SDL 01 under basal conditions, changes in the width, rate of blood flow and blood flow though the trunk of the portal vein before and after intravenous administration of 1 mg glucagon. The width of the trunk of the portal vein did not change significantly during assessment. A statistically significantly increased flow through the portal vein was recorded starting during the 5th minute, and it correlated with the increased velocity of the blood flow. The increased flow persisted to the 20th minute after glucagon administration. The drop of pressure in a wedged position assessed in the hepatic veins after administration of the drug was not significant, the pressure in the free hepatic vein increased insignificantly. On the whole the portohepatic gradient declined by 10.5%, the drop was not significant. Glucagon in pharmacological doses has an early onset of action even in cirrhotic subjects whereby the increased flow through the portal vein does not lead to a rise of the portohepatic gradient. Glucagon administration thus does not increase the risk of haemorrhage from oesophageal varices during acute fibroscopy of the oesophagus and stomach in patients with portal hypertension.

• MeSH
• glukagon farmakologie   MeSH
• jaterní cirhóza komplikace   patofyziologie   MeSH
• lidé MeSH
• portální hypertenze etiologie   MeSH
• portální systém patofyziologie   MeSH
• regionální krevní průtok účinky léků   MeSH
• rychlost toku krve účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• Názvy látek
• glukagon MeSH