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1.
Cell ; 180(2): 278-295.e23, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31978345

RESUMO

Mutations in FAMIN cause arthritis and inflammatory bowel disease in early childhood, and a common genetic variant increases the risk for Crohn's disease and leprosy. We developed an unbiased liquid chromatography-mass spectrometry screen for enzymatic activity of this orphan protein. We report that FAMIN phosphorolytically cleaves adenosine into adenine and ribose-1-phosphate. Such activity was considered absent from eukaryotic metabolism. FAMIN and its prokaryotic orthologs additionally have adenosine deaminase, purine nucleoside phosphorylase, and S-methyl-5'-thioadenosine phosphorylase activity, hence, combine activities of the namesake enzymes of central purine metabolism. FAMIN enables in macrophages a purine nucleotide cycle (PNC) between adenosine and inosine monophosphate and adenylosuccinate, which consumes aspartate and releases fumarate in a manner involving fatty acid oxidation and ATP-citrate lyase activity. This macrophage PNC synchronizes mitochondrial activity with glycolysis by balancing electron transfer to mitochondria, thereby supporting glycolytic activity and promoting oxidative phosphorylation and mitochondrial H+ and phosphate recycling.

2.
Dig Dis Sci ; 2019 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-31875288

RESUMO

BACKGROUND: The prognostic impact of liver steatosis in obese patients is well established. Limited data on the risk factors for and impact of hepatic steatosis in lean patients are available. AIMS: Assess risk factors for liver steatosis in lean patients and investigate its impact on survival. METHODS: Patients without viral hepatitis and with a BMI ≤ 25 kg/m2 undergoing liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) by transient elastography were retrospectively identified. Clinical characteristics and laboratory test results were obtained at the time of LSM/CAP measurement. National death registry data were obtained in order to assess survival. RESULTS: Among n = 218 lean patients, n = 97 (34.5%) showed significant liver steatosis (CAP ≥ 268 dB/m), while n = 184 (65.5%) had no or just mild steatosis (CAP < 268 dB/m). Patients with steatosis had higher GGT (238.0(± 450.3) vs. 112.1(± 180.0) IU/mL; p = 0.013), AST (63(± 67.4) vs. 38.5(± 32.9) IU/mL; p = 0.001), ALT (59.1(± 58.8) vs. 44.3(± 52.7) IU/mL; p = 0.048) and triglyceride levels (120.1(± 80.3) vs. 96.1(± 58.2) mg/dL; p = 0.014), and showed a trend toward more severe fibrosis (LSM 15.6(± 19.5) vs. 12.0(± 15.7) kPa; p = 0.115). In multivariate binary logistic regression analysis, only serum uric acid levels were independently associated with liver steatosis (odds ratio 1.43 per unit mg/dL; 95% CI 1.001-2.054; p = 0.049). During a mean follow-up of 38.9(± 10.6) months, n = 14 patients (5.0%) died. In the absence of advanced fibrosis, survival after 1 year was similar in patients without (98.7%) and with (98.6%) significant steatosis. Patients with advanced fibrosis had worse 1-year survival without concomitant significant steatosis (84.8%) than patients with steatosis (95.8%; log-rank p < 0.001). CONCLUSIONS: High serum uric acid levels increase the risk of liver steatosis in lean patients. Liver fibrosis but not hepatic steatosis is a risk factor for impaired survival in lean patients.

3.
Wien Klin Wochenschr ; 131(17-18): 395-403, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31493100

RESUMO

BACKGROUND: Liver disease impacts on hepatic synthesis of lipoproteins and lipogenesis but data on dyslipidemia during disease progression are limited. We assessed the patterns of dyslipidemia in (i) different liver disease etiologies and discriminated (ii) non-advanced (non-ACLD) from advanced chronic liver disease (ACLD) as it is unclear how progression to ACLD impacts on dyslipidemia-associated cardiovascular risk. METHODS: Patients with alcoholic liver disease (n = 121), hepatitis C (n = 1438), hepatitis B (n = 384), metabolic/fatty liver disease (n = 532), cholestatic liver disease (n = 119), and autoimmune hepatitis (n = 114) were included. Liver stiffness ≥15 kPa defined ACLD. Dyslipidemia was defined as total cholesterol >200 mg/dL, low-density lipoprotein (LDL)-cholesterol >130 mg/dL and triglycerides >200 mg/dL. RESULTS: Across all etiologies, total cholesterol levels were significantly lower in ACLD, when compared to non-ACLD. Accordingly, LDL-cholesterol levels were significantly lower in ACLD due to hepatitis C, hepatitis B, metabolic/fatty liver disease and autoimmune hepatitis. Triglyceride levels did not differ due to disease severity in any etiology. Despite lower total and LDL cholesterol levels in ACLD, etiology-specific dyslipidemia patterns remained similar to non-ACLD. Contrary to this "improved" lipid status in ACLD, cardiovascular comorbidities were more prevalent in ACLD: arterial hypertension was present in 26.6% of non-ACLD and in 55.4% of ACLD patients (p < 0.001), and diabetes was present in 8.1% of non-ACLD and 25.6% of ACLD patients (p < 0.001). CONCLUSION: Liver disease etiology is a major determinant of dyslipidemia patterns and prevalence. Progression to ACLD "improves" serum lipid levels while arterial hypertension and diabetes mellitus are more prevalent. Future studies should evaluate cardiovascular events after ACLD-induced "improvement" of dyslipidemia.


Assuntos
Dislipidemias , Hepatopatias , Adulto , LDL-Colesterol/sangue , Dislipidemias/epidemiologia , Feminino , Humanos , Hepatopatias/epidemiologia , Hepatopatias/etiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Triglicerídeos/sangue
4.
Sci Rep ; 9(1): 11674, 2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31406146

RESUMO

Statins reduce cardiovascular risk. However, "real-life" data on statin use in patients with chronic liver disease and its impact on overall and liver-related survival are limited. Therefore, we assessed 1265 CLD patients stratified as advanced (ACLD) or non-advanced (non-ACLD) stage. Statin indication was evaluated according to the 2013 ACC/AHA guidelines and survival-status was verified by national death registry data. Overall, 122 (9.6%) patients had an indication for statin therapy but did not receive statins, 178 (14.1%) patients were on statins and 965 (76.3%) patients had no indication for statins. Statin underutilization was 34.2% in non-ACLD and 48.2% in ACLD patients. In non-ACLD patients, survival was worse without a statin despite indication as compared to patients on statin or without indication (log-rank p = 0.018). In ACLD patients, statin use did not significantly impact on survival (log-rank p = 0.264). Multivariate cox regression analysis confirmed improved overall survival in patients with statin as compared to patients with indication but no statin (HR 0.225; 95%CI 0.053-0.959; p = 0.044) and a trend towards reduced liver-related mortality (HR 0.088; 95%CI 0.006-1.200; p = 0.068). This was not observed in ACLD patients. In conclusion, guideline-confirm statin use is often withhold from  patients with liver disease and this underutilization is associated with impaired survival in non-ACLD patients.

5.
Liver Int ; 39(1): 127-135, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30107095

RESUMO

BACKGROUND & AIMS: Assessment of hepatic steatosis by transient elastography (TE)-based controlled attenuation parameter (CAP) might predict hepatic decompensation. Therefore, we aimed to evaluate the prognostic value of CAP in patients with compensated advanced chronic liver disease (cACLD) and decompensated cirrhosis (DC). METHODS: A total of 430 patients who underwent TE (liver stiffness ≥10 kPa) and CAP measurements were included in this retrospective analysis. Half of patients (n = 189) underwent simultaneous HVPG measurement. In cACLD patients, first hepatic decompensation was defined by new onset of ascites, hepatic encephalopathy or variceal bleeding. In patients with DC, the following events were considered as further hepatic decompensation: requirement of paracentesis, admission for/development of grade 3/4 hepatic encephalopathy, variceal (re-)bleeding or liver-related death. RESULTS: First hepatic decompensation occurred in 25 of 292 (9%) cACLD patients, while 46 of 138 (33%) DC patients developed further hepatic decompensation during a median follow-up of 22 and 12 months respectively. CAP was not predictive of first (cACLD; per 10 dB/m; hazard ratio [HR]: 0.97, 95% confidence interval [95% CI]: 0.91-1.03, P = 0.321) or further hepatic decompensation (DC; HR: 0.99, 95% CI: 0.94-1.03, P = 0.554) in adjusted analysis. Using the well-established CAP cut-off of ≥248 dB/m for hepatic steatosis, the incidence of first (cACLD; P = 0.065) and further hepatic decompensation (DC; P = 0.578) was similar in patients with hepatic steatosis or without. Serum albumin levels (per mg/dL; HR: 0.83, 95% CI: 0.77-0.89, P < 0.001) and MELD-Na (per point; HR: 1.15, 95% CI: 1.04-1.28, P = 0.006) in cACLD and MELD-Na (per point; HR: 1.12, 95% CI: 1.05-1.19, P < 0.0001) in DC patients were the only parameters independently associated with first and further hepatic decompensation, respectively. CONCLUSION: Controlled attenuation parameter does not predict the development of first (cACLD)/further (DC) hepatic decompensation, while serum albumin levels and MELD-Na are of prognostic value.


Assuntos
Cirrose Hepática/complicações , Falência Hepática/diagnóstico , Fígado/diagnóstico por imagem , Adulto , Idoso , Técnicas de Imagem por Elasticidade , Feminino , Humanos , Falência Hepática/mortalidade , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Albumina Sérica Humana/análise
6.
Int Wound J ; 15(6): 914-920, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29956471

RESUMO

Hypertrophic scar formation because of surgical procedures is associated with higher levels of pain, a lower quality of life, and poor cosmetic outcome and requires more resources in follow-up management. An octenidine-based hydrogel has been shown to modulate immunological function in an in vitro wound model, suggesting an improved scar formation. In this prospective, randomised, observer-blinded, and intra-patient-controlled study, 45 patients who underwent abdominoplasty or mastectomy with transverse rectus abdominis muscle (TRAM) flap reconstruction were given both a standard postoperative wound dressing on one wound side and an octenidine-based hydrogel with transparent film dressing, covered with standard postoperative dressing on the other side. Four instances of hypertrophia were reported in the gel side versus 12 in the standard dressing side. Visual Analogue Scale (VAS) pain scores taken during postoperative dressing changes showed reduced scores on the gel side at all time points. Vancouver Scar Scale (VSS) scores showed improvement in the gel side at 3, 6, and 12 months postoperatively. Skin distensibility measured using a cutometer showed significantly improved measures in gel-treated wounds, similar to measures of healthy skin. Trans-epidermal water loss (TEWL), measured using a tewameter, showed improved values on the gel side soon after surgery, with both the control and the gel side normalising after approximately 6 months. The octenidine-based wound dressing demonstrates improved wound healing associated with a lower incidence of hypertrophic scar formation.


Assuntos
Abdominoplastia/métodos , Anti-Infecciosos/uso terapêutico , Cicatriz Hipertrófica/terapia , Hidrogéis/uso terapêutico , Curativos Oclusivos , Piridinas/uso terapêutico , Cicatrização/fisiologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
7.
Liver Transpl ; 24(1): 112-121, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28752925

RESUMO

Orthotopic liver transplantation (OLT) represents a curative treatment option for end-stage liver disease (ESLD). Although epidemiology of ESLD has recently changed due to the rising prevalence of nonalcoholic fatty liver disease and the decreased burden of hepatitis C virus infections due to highly effective antiviral regimens, the management of portal hypertension (PHT) remains a clinical challenge in the pre- and post-OLT setting. The measurement of the hepatic venous pressure gradient represents the most reliable but invasive tool for assessment of the severity of PHT. Although novel liver ultrasound and magnetic resonance-based elastography methods have been developed, their value to screen for liver fibrosis and PHT in transplanted patients remains to be established. Nonselective beta-blockers represent the cornerstone of medical treatment of PHT, but more studies on their effects on clinical endpoints after OLT are needed. Statins are widely used to treat hyperlipidemia, which is a common condition after OLT. Although a growing body of evidence suggests that statins decrease portal pressure and PHT-related complications in ESLD, studies on potential benefits of statins after OLT are lacking. Finally, transjugular intrahepatic portosystemic shunts (TIPS) are effective in decreasing PHT and seem to decrease mortality on the OLT waiting list. Moreover, TIPS does not have an impact on liver function nor complicate the transplant surgical procedures. TIPS may also be used after OLT, but the evidence is limited. In conclusion, whereas the management of PHT in patients with ESLD is based on strong evidence, further data on the value of noninvasive monitoring tools as well as on medical and invasive treatment options in the post-OLT setting are needed to improve management strategies in patients with recurrent PHT after liver transplantation. Liver Transplantation 24 112-121 2018 AASLD.


Assuntos
Doença Hepática Terminal/cirurgia , Hipertensão Portal/terapia , Transplante de Fígado/efeitos adversos , Antagonistas Adrenérgicos beta/uso terapêutico , Constrição Patológica/prevenção & controle , Doença Hepática Terminal/etiologia , Doença Hepática Terminal/mortalidade , Veias Hepáticas/cirurgia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipertensão Portal/etiologia , Hipertensão Portal/mortalidade , Imunossupressão/efeitos adversos , Imunossupressão/métodos , Fígado/patologia , Fígado/cirurgia , Transplante de Fígado/métodos , Pressão na Veia Porta/efeitos dos fármacos , Veia Porta/efeitos dos fármacos , Veia Porta/fisiopatologia , Veia Porta/cirurgia , Derivação Portossistêmica Transjugular Intra-Hepática/métodos , Cuidados Pós-Operatórios/métodos , Guias de Prática Clínica como Assunto , Cuidados Pré-Operatórios/métodos , Índice de Gravidade de Doença , Transplantes/patologia , Transplantes/cirurgia
8.
United European Gastroenterol J ; 5(8): 1100-1107, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29238588

RESUMO

Background: Transjugular intrahepatic portosystemic shunt (TIPS) implantation is used for treatment of several complications in patients with liver cirrhosis. Recent studies have identified a survival benefit for patients on the waiting list after TIPS implantation, but the optimal time point for TIPS implantation prior to orthotopic liver transplantation (OLT) has not been established. Study: This study retrospectively assessed patients undergoing TIPS implantation before or after listing for OLT at the Medical University of Vienna. n = 98 patients with TIPS on the waiting list between January 1993 and December 2013 were identified (n = 73 (74.5%) pre-listing TIPS, n = 25 (25.5%) post-listing TIPS). A matched control group at the time of OLT without TIPS (n = 60) was included. Results: More patients with post-listing TIPS (28.0%, 7/25) showed clinical improvement and went off-list than patients with pre-listing TIPS (8.2%, 6/73, p = .0119). A similar proportion of patients with pre-listing TIPS (19.2%, 14/73) and post-listing TIPS (20.0%, 5/25) died on the OLT waiting list. Transplant surgery time was similar in patients with and without TIPS: 348(±13) vs. 337(±10) minutes (p = .5139). Estimated 1-year post-transplant survival was similar across all groups (pre-listing TIPS: 76.2%, post-listing TIPS: 86.0%, no TIPS: 91.2%, log-rank p = .1506). Conclusion: TIPS should be considered in all liver transplant candidates, since it can obviate the need for OLT and optimize bridging to OLT.

10.
Int J Surg ; 46: 172-177, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28912105

RESUMO

BACKGROUND: Kidney transplantation represents the treatment of choice for end-stage renal disease (ESRD). However, nephrectomy bears certain short- as well as long-term risks for the healthy, voluntary donor. As obesity is increasing and is a known risk factor for surgical complications, we wanted to assess the impact of BMI on perioperative complication rates and renal function. MATERIALS AND METHODS: We retrospectively assessed patients undergoing living donor kidney nephrectomy at our institution. We identified 289 donors that underwent unilateral nephrectomy between January 2006 and December 2015. Donors were categorized according to their BMI (BMI <25 kg/m2, BMI ≥25/<30 kg/m2, BMI ≥30 kg/m2). Where indicated, analysis of variance (ANOVA) was used to compare groups, a stepwise linear regression model was used to assess impact of BMI on the change of eGFR. RESULTS: 126 donors (43.6%) had a BMI <25 while 120 (41.5%) had a BMI ≥25/<30 and 43 (14.9%) were obese with a BMI ≥30. BMI had no statistically significant influence on the percentage of laparoscopic approach (86.5% vs. 83.3% vs. 88.4%, p = 0.6564), on conversion rates (0% vs. 2.0% vs. 2.6%, p = 0.2879) or postoperative complication rates defined as Clavien Dindo ≥ II (8.7% vs. 13.3% vs. 14.0%, respectively; p = 0.4474). Notably, there were no Grade III or higher complications in any group. There was no difference in pre-operative kidney function, postoperative surgical site infection or systemic infection. BMI and male sex had a statistically significant influence on short-term decline of eGFR. CONCLUSION: Obese donors do not suffer from an increased risk of intraoperative or perioperative complication rates. However, male sex and high BMI are associated with a more pronounced short-term decline in renal function. The impact of BMI on long-term consequences for kidney donors needs to be defined in larger prospective cohorts.


Assuntos
Índice de Massa Corporal , Transplante de Rim , Doadores Vivos , Nefrectomia/efeitos adversos , Adulto , Idoso , Feminino , Taxa de Filtração Glomerular , Humanos , Falência Renal Crônica/cirurgia , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Estudos Retrospectivos , Fatores de Risco
11.
Eur J Gastroenterol Hepatol ; 29(3): 309-316, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27922486

RESUMO

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) can be considered the hepatic manifestation of the metabolic syndrome with nonalcoholic steatohepatitis (NASH) as its progressive form. With increasing prevalence of the metabolic syndrome, NASH cirrhosis is becoming a leading cause for liver transplantation. Some cases of orthotopic liver transplantation (OLT) due to cryptogenic cirrhosis (CC) might show typical features of NASH cirrhosis. Therefore, our aim was to assess recurrence of liver fibrosis in patients transplanted for NASH versus CC after OLT. PATIENTS AND METHODS: Patients transplanted for CC or NASH between 1 January 2004 and 30 September 2015 were included. The histological NAFLD activity score and the NAFLD fibrosis score (NFS) were assessed. RESULTS: In total, 15 and 12 patients underwent OLT because of NASH and CC, respectively. The case load for OLT because of NASH was constantly increasing (n=2 in 2004-2007 vs. n=9 in 2012-2015) whereas decreasing for CC (n=6 in 2004-2007 vs. n=2 in 2012-2015). Patient characteristics at OLT were similar, except for an older age and a higher BMI in NASH patients (59.1±2.2 vs. 51.8±2.9 years, P=0.05; 27.7±1.2 vs. 24.3±0.8 kg/m, P=0.035). Although post-OLT plasma lipid levels and incidence of de-novo hypertension, diabetes, and hyperlipidemia were similar between groups, the post-transplant NFS re-increased in the NASH group (but not in the CC: -0.1317 vs. -1.3645 at 12 months post-OLT, P=0.0400). Post-transplant survival was similar in NASH and CC patients. CONCLUSION: According to the NFS, some NASH patients show recurrence of fibrosis as early as 6-12 months after OLT.


Assuntos
Cirrose Hepática/cirurgia , Transplante de Fígado , Hepatopatia Gordurosa não Alcoólica/cirurgia , Áustria , Biópsia , Progressão da Doença , Feminino , Humanos , Cirrose Hepática/diagnóstico , Cirrose Hepática/etiologia , Cirrose Hepática/mortalidade , Transplante de Fígado/efeitos adversos , Transplante de Fígado/mortalidade , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/mortalidade , Recidiva , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
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