Browsing by Subject "CIRRHOSIS"

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  • Foster, Graham R.; Chayama, Kazuaki; Chuang, Wan-Long; Fainboim, Hugo; Farkkila, Martti; Gadano, Adrian; Gaeta, Giovanni B.; Hezode, Christophe; Inada, Yukiko; Heo, Jeong; Kumada, Hiromitsu; Lu, Sheng-Nan; Marcellin, Patrick; Moreno, Christophe; Roberts, Stuart K.; Strasser, Simone I.; Thompson, Alexander J.; Toyota, Joji; Paik, Seung Woon; Vierling, John M.; Zignego, Anna L.; Cohen, David; McPhee, Fiona; Wind-Rotolo, Megan; Srinivasan, Subasree; Hruska, Matthew; Myler, Heather; Portsmouth, Simon D. (2016)
    Background and purpose: Peginterferon Lambda was being developed as an alternative to alfa interferon for the treatment of chronic hepatitis C virus (HCV) infection. We compared peginterferon Lambda-1a plus ribavirin (Lambda/RBV) and Lambda/RBV plus daclatasvir (DCV; pangenotypic NS5A inhibitor) with peginterferon alfa-2a plus RBV (alfa/RBV) in treatment-naive patients with HCV genotype 2 or 3 infection. Methods: In this multicenter, double-blind, phase 3 randomized controlled trial, patients were assigned 2:2:1 to receive 24 weeks of Lambda/RBV, 12 weeks of Lambda/RBV + DCV, or 24 weeks of alfa/RBV. The primary outcome measure was sustained virologic response at post-treatment Week 12 (SVR12). Results: Overall, 874 patients were treated: Lambda/RBV, n = 353; Lambda/RBV + DCV, n = 349; alfa/RBV, n = 172. Patients were 65 % white and 33 % Asian, 57 % male, with a mean age of 47 years; 52 % were infected with genotype 2 (6 % cirrhotic) and 48 % with genotype 3 (9 % cirrhotic). In the Lambda/RBV + DCV group, 83 % (95 % confidence interval [CI] 78.5, 86.5) achieved SVR12 (90 % genotype 2, 75 % genotype 3) whereas SVR12 was achieved by 68 % (95 % CI 63.1, 72.9) with Lambda/RBV (72 % genotype 2, 64 % genotype 3) and 73 % (95 % CI 66.6, 79.9) with peginterferon alfa/RBV (74 % genotype 2, 73 % genotype 3). Lambda/RBV + DCV was associated with lower incidences of flu-like symptoms, hematological abnormalities, and discontinuations due to adverse events compared with alfa/RBV. Conclusion: The 12-week regimen of Lambda/RBV + DCV was superior to peginterferon alfa/RBV in the combined population of treatment-naive patients with genotype 2 or 3 infection, with an improved tolerability and safety profile compared with alfa/RBV.
  • Marini, Selena; Santangeli, Olena; Saarelainen, Pirjo; Middleton, Benita; Chowdhury, Namrata; Skene, Debra J.; Costa, Rodolfo; Porkka-Heiskanen, Tarja; Montagnese, Sara (2017)
    Patients with liver cirrhosis can develop hyperammonemia and hepatic encephalopathy (HE), accompanied by pronounced daytime sleepiness. Previous studies with healthy volunteers show that experimental increase in blood ammonium levels increases sleepiness and slows the waking electroencephalogram. As ammonium increases adenosine levels invitro, and adenosine is a known regulator of sleep/wake homeostasis, we hypothesized that the sleepiness-inducing effect of ammonium is mediated by adenosine. Eight adult male Wistar rats were fed with an ammonium-enriched diet for 4 weeks; eight rats on standard diet served as controls. Each animal was implanted with electroencephalography/electromyography (EEG/EMG) electrodes and a microdialysis probe. Sleep EEG recording and cerebral microdialysis were carried out at baseline and after 6 h of sleep deprivation. Adenosine and metabolite levels were measured by high-performance liquid chromatography (HPLC) and targeted LC/MS metabolomics, respectively. Baseline adenosine and metabolite levels (12 of 16 amino acids, taurine, t4-hydroxy-proline, and acetylcarnitine) were lower in hyperammonemic animals, while putrescine was higher. After sleep deprivation, hyperammonemic animals exhibited a larger increase in adenosine levels, and a number of metabolites showed a different time-course in the two groups. In both groups the recovery period was characterized by a significant decrease in wakefulness/increase in NREM and REM sleep. However, while control animals exhibited a gradual compensatory effect, hyperammonemic animals showed a significantly shorter recovery phase. In conclusion, the adenosine/metabolite/EEG response to sleep deprivation was modulated by hyperammonemia, suggesting that ammonia affects homeostatic sleep regulation and its metabolic correlates.
  • Williams, Monique; Valayannopoulos, Vassili; Altassan, Ruqaiah; Chung, Wendy K.; Heijboer, Annemieke C.; Keng, Wei Teik; Lapatto, Risto; McClean, Patricia; Mulder, Margot F.; Tylki-Szymanska, Anna; Walenkamp, Marie-Jose E.; Alfadhel, Majid; Alakeel, Hajar; Salomons, Gajja S.; Eyaid, Wafaa; Wamelink, Mirjam M. C. (2019)
    BackgroundTransaldolase deficiency (TALDO-D) is a rare autosomal recessive inborn error of the pentose phosphate pathway. Since its first description in 2001, several case reports have been published, but there has been no comprehensive overview of phenotype, genotype, and phenotype-genotype correlation. MethodsWe performed a retrospective questionnaire and literature study of clinical, biochemical, and molecular data of 34 patients from 25 families with proven TALDO-D. In some patients, endocrine abnormalities have been found. To further evaluate these abnormalities, we performed biochemical investigations on blood of 14 patients. Results and conclusionsMost patients (n =22) had an early-onset presentation (prenatally or before 1 month of age); 12 patients had a late-onset presentation (3 months to 9 years). Main presenting symptoms were intrauterine growth restriction, dysmorphic facial features, congenital heart disease, anemia, thrombocytopenia, and hepato(spleno)megaly. An older sib of two affected patients was asymptomatic until the age of 9 years, and only after molecular diagnosis was hepatomegaly noted. In some patients, there was gonadal dysfunction with low levels of testosterone and secondary luteinizing hormone (LH) and follicle-stimulating hormone (FSH) abnormalities later in life. This overview provides information that can be helpful for managing patients and counseling families regarding prognosis. Diagnostic guidelines, possible genotype-phenotype correlations, treatment options, and pathophysiological disease mechanisms are proposed.
  • Kantola, Taru; Mäklin, Suvi; Koivusalo, Anna-Maria; Räsänen, Pirjo; Rissanen, Anne; Roine, Risto; Sintonen, Harri; Höckerstedt, Krister; Isoniemi, Helena (2010)
  • Dudel, Christian; Myrskylä, Mikko (2020)
    Background Markov models are a key tool for calculating expected time spent in a state, such as active life expectancy and disabled life expectancy. In reality, individuals often enter and exit states recurrently, but standard analytical approaches are not able to describe this dynamic. We develop an analytical matrix approach to calculating the expected number and length of episodes spent in a state. Methods The approach we propose is based on Markov chains with rewards. It allows us to identify the number of entries into a state and to calculate the average length of episodes as total time in a state divided by the number of entries. For sampling variance estimation, we employ the block bootstrap. Two case studies that are based on published literature illustrate how our methods can provide new insights into disability dynamics. Results The first application uses a classic textbook example on prednisone treatment and liver functioning among liver cirrhosis patients. We replicate well-known results of no association between treatment and survival or recovery. Our analysis of the episodes of normal liver functioning delivers the new insight that the treatment reduced the likelihood of relapse and extended episodes of normal liver functioning. The second application assesses frailty and disability among elderly people. We replicate the prior finding that frail individuals have longer life expectancy in disability. As a novel finding, we document that frail individuals experience three times as many episodes of disability that were on average twice as long as the episodes of nonfrail individuals. Conclusions We provide a simple analytical approach for calculating the number and length of episodes in Markov chain models. The results allow a description of the transition dynamics that goes beyond the results that can be obtained using standard tools for Markov chains. Empirical applications using published data illustrate how the new method is helpful in unraveling the dynamics of the modeled process.
  • Sahlman, Perttu; Nissinen, Markku; Puukka, Pauli; Jula, Antti; Salomaa, Veikko; Männistö, Satu; Lundqvist, Annamari; Valsta, Liisa; Perola, Markus; Färkkilä, Martti; Åberg, Fredrik (2019)
    Background and Aim Liver disease is traditionally categorized as alcoholic and non-alcoholic. We studied various risk factors predictive of advanced non-viral liver disease in general population and analyzed the interaction between these factors and alcohol consumption. Methods Persons without underlying liver disease who participated in the Health2000 or FINRISK studies 1992-2012 comprised a cohort of 41 260 individuals. Pattern of alcohol consumption and metabolic, lifestyle-related, and anthropometric parameters were analyzed with Cox regression analysis using severe liver disease hospitalization, cancer, or death as end-point. Viral liver diseases were excluded. Results A total of 355 liver events occurred during the mean 12.4-year follow-up (511 789 person-years). In the multivariate model, age (hazard ratio [HR] 1.03, P = 0.0083 for men; HR 1.04, P = 0.0198 for women), waist-to-hip ratio (WHR) (HR 1.52, P = 0.0006 for men; HR 1.58, P = 0.0167 for women), patatin-like phospholipase-containing domain 3 mutations (HR 1.9, P = 0.024 for men; HR 2.7, P = 0.0109 for women), and weekly binge drinking (HR 2.4, P = 0.0024 for men; HR 7.4, P <0.0001 for women) predicted development of severe liver disease. Among men, diabetes (HR 2.7, P = 0.0002), average alcohol consumption (HR for 10 g/day 1.1, P = 0.0022), non-married status (HR 1.9, P = 0.0397 for single; HR 2.4, P = 0.0002 for widowed/separated), and serum high-density lipoprotein (HR 2.2, P = 0.0022) and non-high-density lipoprotein cholesterol (HR 1.2, P = 0.0237) were additional risk factors. Alcohol intake increased the risk especially among persons with high WHR (P for interaction 0.009). Conclusions Age, patatin-like phospholipase-containing domain 3 haplotype, and WHR increase the risk for development of severe liver disease. We found strong synergism between alcohol and central obesity. Binge drinking is an additional risk factor.
  • The International PSC Study Group; The UK PSC Consortium; Alberts, Rudi; de Vries, Elisabeth M. G.; Goode, Elizabeth C.; Jiang, Xiaojun; Sampaziotis, Fotis; Rombouts, Krista; Böttcher, Katrin; Folseraas, Trine; Weismüller, Tobias J.; Mason, Andrew L.; Wang, Weiwei; Alexander, Graeme; Alvaro, Domenico; Bergquist, Annika; Björkström, Niklas K.; Beuers, Ulrich; Björnsson, Einar; Boberg, Kirsten Muri; Bowlus, Christopher L.; Bragazzi, Maria C.; Carbone, Marco; Chazouilleres, Olivier; Cheung, Angela; Dalekos, Georgios; Eaton, John; Eksteen, Bertus; Ellinghaus, David; Färkkilä, Martti Antero; Festen, Eleonora A. M.; Floreani, Annarosa; Franceschet, Irene; Gotthardt, Daniel Nils; Hirschfield, Gideon M.; van Hoek, Bart; Holm, Kristian; Hohenester, Simon; Hov, Johannes Roksund; Imhann, Floris; Invernizzi, Pietro; Juran, Brian D.; Lenzen, Henrike; Lieb, Wolfgang; Liu, Jimmy Z.; Marschall, Hanns-Ulrich; Marzioni, Marco; Melum, Espen; Milkiewicz, Piotr; Müller, Tobias; Pares, Albert; Rupp, Christian; Rust, Christian; Sandford, Richard N.; Schramm, Christoph; Schreiber, Stefan; Schrumpf, Erik; Silverberg, Mark S.; Srivastava, Brijesh; Sterneck, Martina; Teufel, Andreas; Vallier, Ludovic; Verheij, Joanne; Vila, Arnau Vich; de Vries, Boudewijn; Zachou, Kalliopi; Chapman, Roger W.; Manns, Michael P.; Pinzani, Massimo; Rushbrook, Simon M.; Lazaridis, Konstantinos N.; Franke, Andre; Anderson, Carl A.; Karlsen, Tom H.; Ponsioen, Cyriel Y.; Weersma, Rinse K. (2018)
    Objective Primary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications. Design We collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients-obtained using the Illumina immunochip-with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes. Results We identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07x10(-9)). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells. Conclusion We present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.
  • Puustinen, Lauri; Barner-Rasmussen, Nina; Pukkala, Eero; Farkkila, Martti (2019)
    Background: Epidemiological studies of autoimmune hepatitis are scarce and often based on single centre registries. Aims: We conducted a nationwide register study of incidence, prevalence, survival, and causes of death of autoimmune hepatitis patients in Finland. Methods: Autoimmune hepatitis cases 1995-2015 were retrieved from the national database of special reimbursements for drugs costs. Data on causes of death were retrieved from Statistics Finland. Results: After incomplete registration of AIH during the first years, the incidence of autoimmune hepatitis stabilised to 1.1/100,000 person-years (1.6 in women and 0.52 in men) in 2008-2015. The prevalence of autoimmune hepatitis at the end of 2015 was 14.3/100,000, 23.0/100,000 in women and 6.6/100,000 in men. The all-cause standardized mortality ratio (SMR) of autoimmune hepatitis patients was 1.81 (95% confidence interval (CI) 1.47-2.20). The SMR was increased in all age groups and in both sexes. The SMR for hepatocellular carcinoma was 20.6 (95% CI 10.3-36.8), and for digestive diseases in overall 13.5 (95% CI 8.2-20.8), constituting mainly from autoimmune hepatitis and liver cirrhosis. Conclusion: Incidence of autoimmune hepatitis has remained stable, with clear female predominance. Autoimmune hepatitis is associated with a markedly increased risk of death with hepatocellular cancer forming the greatest risk. (C) 2019 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
  • Hakkarainen, Antti; Puustinen, Lauri; Kivisaari, Reetta; Boyd, Sonja; Nieminen, Urpo; Arkkila, Perttu; Lundbom, Nina (2017)
    Purpose: To study liver P-31 MRS, histology, transient elastography, and liver function tests in patients with virus C hepatitis (HCV) or autoimmune hepatitis (AIH) to test the hypothesis that P-31 MR metabolic profile of these diseases differ. Materials and methods: 25 patients with HCV (n = 12) or AIH (n = 13) underwent proton decoupled P-31 MRS spectroscopy performed on a 3.0 T MR imager. Intensities of phosphomonoesters (PME) of phosphoethanolamine (PE) and phosphocholine (PC), phosphodiesters (PDE) of glycerophosphoethanolamine( GPE) and glycerophosphocholine (GPC), and gamma, alpha and beta resonances of adenosine triphosphate (ATP), and nicotinamide adenine dinucleotide phosphate (NADPH) were determined. Liver stiffness was measured by transient elastography. Inflammation and fibrosis were staged according to METAVIR from biopsy samples. Activities of alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALT) and thromboplastin time (TT) were determined from serum samples. Results: PME had a stronger correlation with AST (z = 1.73, p = 0.04) and ALT (z = 1.77, p = 0.04) in HCV than in AIH patients. PME, PME/PDE, PE/GPE correlated positively and PDE negatively with inflammatory activity. PE, PC and PME correlated positively with liver function tests. Conclusion: P-31-MRS suggests a more serious liver damage in HCV than in AIH with similar histopathological findings. P-31-MRS is more sensitive in detecting inflammation than fibrosis in the liver. (C) 2017 Elsevier B.V. All rights reserved.
  • Holmer, Magnus; Melum, Espen; Isoniemi, Helena; Ericzon, Bo-Göran; Castedal, Maria; Nordin, Arno; Schultz, Nicolai Aagaard; Rasmussen, Allan; Line, Pal-Dag; Stål, Per; Bennet, William; Hagström, Hannes (2018)
    Background & Aims Nonalcoholic fatty liver disease(NAFLD) is the second most common cause of liver transplantation in the US. Data on NAFLD as a liver transplantation indication from countries with lower prevalences of obesity are lacking. We studied the temporal trends of NAFLD as an indication for liver transplantation in the Nordic countries, and compared outcomes for patients with NAFLD to patients with other indications for liver transplantation. MethodResultsPopulation-based cohort study using data from the Nordic Liver Transplant Registry on adults listed for liver transplantation between 1994 and 2015. NAFLD as the underlying indication for liver transplantation was defined as a listing diagnosis of NAFLD/nonalcoholic steatohepatitis, or cryptogenic cirrhosis with a body mass index 25kg/m(2) and absence of other liver diseases. Waiting time for liver transplantation, mortality and withdrawal from the transplant waiting list were registered. Survival after liver transplantation was calculated using multivariable Cox regression, adjusted for age, sex, body mass index and model for end-stage liver disease. A total of 4609 patients listed for liver transplantation were included. NAFLD as the underlying indication for liver transplantation increased from 2.0% in 1994-1995 to 6.2% in 2011-2015 (P=.01) and was the second most rapidly increasing indication. NAFLD patients had higher age, model for end-stage liver disease and body mass index when listed for liver transplantation, but overall survival after liver transplantation was comparable to non--NAFLD patients (aHR 1.03, 95% CI 0.70-1.53 P=.87). ConclusionNAFLD is an increasing indication for liver transplantation in the Nordic countries. Despite more advanced liver disease, NAFLD patients have a comparable survival to other patients listed for liver transplantation.
  • Arshad, Freeha; Ickx, Brigitte; van Beem, Rachel T.; Polak, Wojciech; Grune, Frank; Nevens, Frederik; Ilmakunnas, Minna; Koivusalo, Anna-Maria; Isoniemi, Helena; Strengers, Paul F. W.; Groen, Henk; Hendriks, Herman G. D.; Lisman, Ton; Pirenne, Jacques; Porte, Robert J. (2013)
    Background: In patients with cirrhosis, the synthesis of coagulation factors can fall short, reflected by a prolonged prothrombin time. Although anticoagulants factors are decreased as well, blood loss during orthotopic liver transplantation can still be excessive. Blood loss during orthotopic liver transplantation is currently managed by transfusion of red blood cell concentrates, platelet concentrates, fresh frozen plasma, and fibrinogen concentrate. Transfusion of these products may paradoxically result in an increased bleeding tendency due to aggravated portal hypertension. The hemostatic effect of these products may therefore be overshadowed by bleeding complications due to volume overload. In contrast to these transfusion products, prothrombin complex concentrate is a low-volume highly purified concentrate, containing the four vitamin K dependent coagulation factors. Previous studies have suggested that administration of prothrombin complex concentrate is an effective method to normalize a prolonged prothrombin time in patients with liver cirrhosis. We aim to investigate whether the pre-operative administration of prothrombin complex concentrate in patients undergoing liver transplantation for end-stage liver cirrhosis, is a safe and effective method to reduce perioperative blood loss and transfusion requirements. Methods/Design: This is a double blind, multicenter, placebo-controlled randomized trial. Cirrhotic patients with a prolonged INR (>= 1.5) undergoing liver transplantation will be randomized between placebo or prothrombin complex concentrate administration prior to surgery. Demographic, surgical and transfusion data will be recorded. The primary outcome of this study is RBC transfusion requirements. Discussion: Patients with advanced cirrhosis have reduced plasma levels of both pro- and anticoagulant coagulation proteins. Prothrombin complex concentrate is a low-volume plasma product that contains both procoagulant and anticoagulant proteins and transfusion will not affect the volume status prior to the surgical procedure. We hypothesize that administration of prothrombin complex concentrate will result in a reduction of perioperative blood loss and transfusion requirements. Theoretically, the administration of prothrombin complex concentrate may be associated with a higher risk of thromboembolic complications. Therefore, thromboembolic complications are an important secondary endpoint and the occurrence of this type of complication will be closely monitored during the study.
  • Åberg, Fredrik; Puukka, Pauli; Salomaa, Veikko; Männistö, Satu; Lundqvist, Annamari; Valsta, Liisa; Perola, Markus; Färkkilä, Martti; Jula, Antti (2020)
    Background and Aims The effects of alcohol use in nonalcoholic fatty liver disease are unclear. We investigated the impact of alcohol use in fatty liver disease on incident liver, cardiovascular, and malignant disease, as well as death. Approach and Results Our study comprised 8,345 persons with hepatic steatosis (fatty liver index >60) who participated in health-examination surveys (FINRISK 1992-2012 or Health 2000), with available data on baseline alcohol intake. Main exclusions were baseline clinical liver disease, viral hepatitis, ethanol intake >50 g/day, and current abstainers. Data were linked with national registers for hospital admissions, malignancies, and death regarding liver, cardiovascular, and malignant disease, as well as all-cause death. Adjustment were for multiple confounders. Alcohol consumption showed a dose-dependent risk increase for incident advanced liver disease and malignancies. Consuming 10-19 g/day of alcohol in general or 0-9 g/day as nonwine beverages doubled the risk for advanced liver disease compared to lifetime abstainers. In contrast, alcohol intake up to 49 g/day was associated with a 22%-40% reduction of incident cardiovascular disease (CVD). We observed a J-shaped association between alcohol intake and all-cause death with a maximal risk reduction of 21% (95% confidence interval, 5%-34%) at alcohol intake of 0-9 g/day compared to lifetime abstainers. However, these benefits on CVD and mortality were only observed in never smokers. Alcohol intake >30 g/day yielded increased risk estimates for mortality compared to lifetime abstainers. In a subpopulation with longitudinal data, alcohol intake remained stable over time in >80% of subjects. Conclusions Even low alcohol intake in fatty liver disease is associated with increased risks for advanced liver disease and cancer. Low to moderate alcohol use is associated with reduced mortality and CVD risk but only among never smokers.
  • Mannisto, Ville; Färkkilä, Martti; Pussinen, Pirkko; Jula, Antti; Männistö, Satu; Lundqvist, Annamari; Valsta, Liisa; Salomaa, Veikko; Perola, Markus; Åberg, Fredrik (2019)