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BACKGROUND: Few studies examined the outcome of patients with hepatitis C virus (HCV)-related cirrhosis who developed hepatocellular carcinoma (HCC). The relative weight as determinant of death for cancer vs end-stage liver disease (ESLD) and the benefit of HCV eradication remain undefined. This multicentre, retrospective analysis evaluates overall survival (OS), rate of decompensation and tumour recurrence in compensated HCC patients treated with interferon (IFN) according to HCV status since HCC diagnosis. METHODS: Two groups of patients with HCV-related cirrhosis and HCC were followed since HCC diagnosis: (i) compensated cirrhotics with prior sustained virological response (SVR) on IFN-based regimens (N=19); (ii) compensated cirrhotics without SVR (viraemic) (N=156). RESULTS: Over a median follow-up of 3.0 years since the onset of HCC, OS was longer for HCC patients with SVR than for viraemic patients (log-rank P=.004). The 5-year OS rate was 65.9% in patients with SVR vs 31.9% in viraemic patients. Similar trends were reported for hepatic decompensation (log-rank P=.01) and tumour recurrence (log-rank P=.01). These findings were confirmed at multivariable and propensity score analysis. At propensity analysis, 0/19 compensated patients with SVR died for ESLD vs 7/19 (37%) viraemic patients (P=.004). HCC mortality was similar in the two groups. CONCLUSIONS: Hepatocellular carcinoma patients with prior SVR and compensated cirrhosis at the time of tumour diagnosis have prolonged OS than viraemic patients. Given the lack of cirrhosis progression, no SVR patient ultimately died for ESLD while this condition appears the main cause of death among viraemic patients.
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Antivirais/uso terapêutico , Carcinoma Hepatocelular/terapia , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Interferons/uso terapêutico , Neoplasias Hepáticas/terapia , Ribavirina/uso terapêutico , Resposta Viral Sustentada , Idoso , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/virologia , Quimioterapia Combinada , Feminino , Hepacivirus/crescimento & desenvolvimento , Hepatite C/diagnóstico , Hepatite C/mortalidade , Hepatite C/virologia , Humanos , Itália , Estimativa de Kaplan-Meier , Cirrose Hepática/diagnóstico , Cirrose Hepática/mortalidade , Cirrose Hepática/virologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Recidiva Local de Neoplasia , Pontuação de Propensão , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND & AIMS: Life expectancy of patients with compensated hepatitis C virus (HCV) cirrhosis achieving sustained virologic response (SVR) is limited by liver events as compared to the general population. Thus, survival benefit of SVR remains to be measured. METHODS: The study includes prospective surveillance data from three cohorts of Italian patients with compensated HCV cirrhosis who achieved SVR on an interferon-based (IFN) regimen, compared to simultaneously observed non-SVR, untreated and decompensated patients. Overall survival was calculated from the date of start of IFN to death. The number of deaths expected during the at-risk period was determined by applying age- and sex-specific mortality rates recorded in Italy for person-years adequate for the enrolment period. The standardized mortality ratio (SMR) determined the relative risk of death over that of the age and sex matched general population. RESULTS: Overall, 28/181 patients followed-up for a median period of 9.6years (range 1-25years) died. The 10 and 20-year overall survival rates for the whole series were 90.9% (95% CI, 84.3-94.8) and 62.9% (95% CI, 45.9-75.9), respectively. The number of expected deaths in the corresponding age and sex matched general population was 28.1, corresponding to a SMR=1.00 (95% CI, 0.72-1.35), with an SMR for non-SVR patients of 3.85 (95% CI, 3.43-4.30), for untreated of 3.01 (95% CI, 2.64-3.42) and for decompensated of 6.70 (95% CI, 5.39-8.22). CONCLUSIONS: Patients with compensated HCV cirrhosis achieving SVR by IFN obtain a main benefit levelling their survival curve to that of the general population. Wider applicability of IFN-free regimens will possibly make this achievement more generalizable.
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Hepatite C Crônica/mortalidade , Cirrose Hepática/mortalidade , Adulto , Idoso , Feminino , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Humanos , Interferons/uso terapêutico , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Taxa de Sobrevida , Resposta Viral SustentadaRESUMO
OBJECTIVE: To evaluate the fasting and postprandial serum bile acid composition in patients with cystic fibrosis-associated liver disease (CFLD) after chronic administration of ursodeoxycholic acid (UDCA) (20 mg/kg/day). The aim was to specifically focus on the extent of biotransformation of UDCA to its hepatotoxic metabolite, lithocholic acid, because of recent concerns regarding the safety of long-term, high-dose UDCA treatment for CFLD. STUDY DESIGN: Twenty patients with CFLD (median age 16 years, range: 2.4-35.0) prescribed UDCA therapy for at least 2 years were studied. Total and individual serum bile acids were measured by stable-isotope dilution mass spectrometry, in fasting and 2-hour postprandial samples taken during chronic UDCA (20 mg/kg/day) administration. RESULTS: During chronic UDCA administration (median duration 8 years, IQR: 6-16), UDCA became the predominant serum bile acid in all patients (median, IQR: 3.17, 1.25-5.56 µmol/L) and chenodeoxycholic acid concentrations were greater than cholic acid (1.86, 1.00-4.70 µmol/L vs 0.40, 0.24-2.71 µmol/L). The secondary bile acids, deoxycholate and lithocholate, were present in very low concentrations in fasted serum (<0.05 µmol/L). After UDCA administration, 2-hour postprandial concentrations of both UDCA and chenodeoxycholic acid significantly increased (P < .01), but no significant changes in serum lithocholic acid concentrations were observed. CONCLUSION: These data do not support recent suggestions that enhanced biotransformation of UDCA to the hepatotoxic secondary bile acid lithocholic occurs when patients with CFLD are treated with relatively high doses of UDCA.
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Ácidos e Sais Biliares/sangue , Fibrose Cística/tratamento farmacológico , Ácido Litocólico/sangue , Hepatopatias/tratamento farmacológico , Ácido Ursodesoxicólico/uso terapêutico , Adolescente , Adulto , Biotransformação , Criança , Pré-Escolar , Fibrose Cística/sangue , Ácido Desoxicólico/sangue , Feminino , Humanos , Hepatopatias/sangue , Masculino , Espectrometria de Massas em Tandem , Ácido Ursodesoxicólico/efeitos adversos , Adulto JovemRESUMO
Extracorporeal membrane oxygenation (ECMO) is required for patients with refractory cardiac or respiratory failure. Inadequate securement of ECMO cannulae may lead to adverse events, ranging from line kinking to catastrophic accidents, such as air entrainment into the circuit or massive bleeding. Furthermore, the micro-motion of the cannulae at the entry site might increase the risk of local infections. Since 2015, we implemented a written protocol for management of ECMO cannulae and tubing, which specifically includes the securement of each cannula with three sutureless devices. The aim of the present study was to retrospectively assess cannulae micro-motion and the rate of bleeding events at the insertion site. Secondarily we aimed to evaluate the impact of prone positioning maneuvers during ECMO on these events. We performed a single-centre retrospective analysis of prospectively collected data on nursing care of ECMO cannulae. We included adult patients treated with veno-venous (V-V) or veno-arterial (V-A) ECMO between 2015 and 2018 in our general intensive care unit. The distance between the insertion site and the end of the wire-wound part of the cannula was recorded daily. Variations of this distance (defined as "cannula micro-motion") were recorded. Forty-five ECMO consecutive adult patients (40 V-V and 5 V-A) were included. No accidental cannula dislodgement was recorded. Median daily "cannula micro-motion" was 0.0 (-0.5 to 0.2) cm, without any significant difference between ECMO configuration, cannula type, and insertion site. Twelve patients (26%) presented at least one bleeding episode at cannula insertion site, none of which required surgical intervention. In the subgroup of patients who underwent prone positioning, no difference in cannulae micro-motion was recorded. An ECMO nursing protocol for cannulae management providing sutureless devices for cannula and tubing securement allows safe line stabilization, with the potential to reduce complications related to ECMO vascular access.
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Cateterismo , Oxigenação por Membrana Extracorpórea , Adulto , Humanos , Estudos de Coortes , Estudos Retrospectivos , CânulaRESUMO
Alterations of cholesterol homeostasis represent important risk factors for atherosclerosis and cardiovascular disease. Different clinical-experimental approaches have been devised to study the metabolism of cholesterol and particularly the synthesis of bile acids, its main catabolic products. Most evidence in humans has derived from studies utilizing the administration of labeled sterols; these have several advantages over in vitro assay of enzyme activity and expression, requiring an invasive procedure such as a liver biopsy, or the determination of fecal sterols, which is cumbersome and not commonly available. Pioneering evidence with administration of radioactive sterol derivatives has allowed to characterize the alterations of cholesterol metabolism and degradation in different situations, including spontaneous disease conditions, aging, and drug treatment. Along with the classical isotope dilution methodology, other approaches were proposed, among which isotope release following radioactive substrate administration. More recently, stable isotope studies have allowed to overcome radioactivity exposure. Isotope enrichment studies during tracer infusion has allowed to characterize changes in the degradation of cholesterol via the "classical" and the "alternative" pathways of bile acid synthesis. Evidence brought by tracer studies in vivo, summarized here, provides an exceptional tool for the investigation of sterol metabolism, and integrate the studies in vitro on human tissue.
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Ácidos e Sais Biliares/metabolismo , Colesterol/metabolismo , Fígado/metabolismo , Compostos Radiofarmacêuticos/metabolismo , Esteróis/metabolismo , Humanos , Lipólise , Traçadores RadioativosRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths. Early-stage disease is treated with curative intent, but most patients present with advanced HCC, which carries a poor prognosis. Viscum album extracts (VAE) are used by cancer patients as an adjunct treatment or palliation. CASE PRESENTATION: A 51-year-old female presented with relapsing multifocal HCC. She declined palliative treatment and commenced intravenous VAE treatment in conjunction with intravenous hepato-protective L-ornithine-L-aspartate (LOLA). She experienced a significant improvement of life-quality and performance status. After 3 months, a significant regression was noted on computerized tomography, and α-fetoprotein was in normal range. Imaging 11 months later confirmed a complete regression. The VAE and LOLA treatment continues to date. The patient had no other cancer-directed therapy. The regression is sustained for more than 5 years at publication, confirmed by regular imaging and serology. The patient is experiencing an unrestricted quality of life. CONCLUSION: Complete regression of advanced HCC is rare. Responses of HCC to VAE treatment have been reported before. However, this is the first documented case with a complete and durable regression of an HCC under treatment with VAE. Further studies should evaluate VAE treatment in HCC, especially when administered in forms as reported here.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Viscum album , Feminino , Humanos , Pessoa de Meia-Idade , Carcinoma Hepatocelular/tratamento farmacológico , Qualidade de Vida , Extratos Vegetais/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Recidiva Local de NeoplasiaRESUMO
Patients with acute pancreatitis (AP) often require ICU admission, especially when signs of multiorgan failure are present, a condition that defines AP as severe. This disease is characterized by a massive pancreatic release of pro-inflammatory cytokines that causes a systemic inflammatory response syndrome and a profound intravascular fluid loss. This leads to a mixed hypovolemic and distributive shock and ultimately to multiorgan failure. Aggressive fluid resuscitation is traditionally considered the mainstay treatment of AP. In fact, all available guidelines underline the importance of fluid therapy, particularly in the first 24-48 h after disease onset. However, there is currently no consensus neither about the type, nor about the optimal fluid rate, total volume, or goal of fluid administration. In general, a starting fluid rate of 5-10 ml/kg/h of Ringer's lactate solution for the first 24 h has been recommended. Fluid administration should be aggressive in the first hours, and continued only for the appropriate time frame, being usually discontinued, or significantly reduced after the first 24-48 h after admission. Close clinical and hemodynamic monitoring along with the definition of clear resuscitation goals are fundamental. Generally accepted targets are urinary output, reversal of tachycardia and hypotension, and improvement of laboratory markers. However, the usefulness of different endpoints to guide fluid therapy is highly debated. The importance of close monitoring of fluid infusion and balance is acknowledged by most available guidelines to avoid the deleterious effect of fluid overload. Fluid therapy should be carefully tailored in patients with severe AP, as for other conditions frequently managed in the ICU requiring large fluid amounts, such as septic shock and burn injury. A combination of both noninvasive clinical and invasive hemodynamic parameters, and laboratory markers should guide clinicians in the early phase of severe AP to meet organ perfusion requirements with the proper administration of fluids while avoiding fluid overload. In this narrative review the most recent evidence about fluid therapy in severe AP is discussed and an operative algorithm for fluid administration based on an individualized approach is proposed.
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UNLABELLED: The incidence of de novo development of esophageal varices (EV) in patients with compensated liver cirrhosis has been determined by few studies in the short term and never in the long term. The aims of the present study were to determine the incidence and the risk factors associated with the development of EV and to assess whether antiviral treatment and achievement of sustained virologic response (SVR) may prevent de novo EV development in patients with HCV-induced cirrhosis. We studied 218 patients with compensated EV-free, HCV-induced cirrhosis consecutively enrolled between 1989 and 1992 at three referral centers in Milan, Italy. Endoscopic surveillance was performed at 3-year intervals according to international guidelines. SVR was defined as undetectable serum HCV-RNA 24 weeks after treatment discontinuation. During a median follow-up of 11.4 years, 149/218 (68%) patients received antiviral treatment and 34 (22.8%) achieved SVR. None of the SVR patients developed EV compared with 22 (31.8%) of the 69 untreated subjects (P < 0.0001) and 45 (39.1%) of the 115 non-SVR patients (P < 0.0001). On multivariate analysis, HCV genotype 1b (hazard ratio [HR] 2.40; 95% confidence interval [CI] 1.17-4.90) and baseline model for end-stage liver disease (MELD) score (HR 1.20; 95% CI 1.07-1.35 for 1 point increase) were independent predictors of EV. CONCLUSION: In the long term, the achievement of SVR prevents the development of EV in patients with compensated HCV-induced cirrhosis. Therefore, in these patients, endoscopic surveillance can be safely delayed or avoided. Genotype 1b infection and MELD score identify the subset of patients at higher risk of EV development who need tailored endoscopic surveillance.
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Antivirais/uso terapêutico , Varizes Esofágicas e Gástricas/prevenção & controle , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Cirrose Hepática/complicações , Idoso , Carcinoma Hepatocelular/epidemiologia , Varizes Esofágicas e Gástricas/epidemiologia , Varizes Esofágicas e Gástricas/etiologia , Feminino , Seguimentos , Humanos , Incidência , Itália/epidemiologia , Cirrose Hepática/virologia , Neoplasias Hepáticas/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de RiscoRESUMO
OBJECTIVES: The identification of prognostic factors associated with mortality is crucial in any clinical setting. METHODS: We enrolled in a prospective study 352 patients with compensated hepatitis C virus (HCV)-induced cirrhosis, consecutively observed between 1989 and 1992. At entry, patients underwent upper endoscopy to detect esophageal varices, and were then surveilled by serial clinical and ultrasonographic examination. The model for end-stage liver disease (MELD) score was calculated with information collected at enrollment. Baseline predictors and intercurrent events associated with mortality were assessed using the Cox regression model. RESULTS: During a median follow-up of 14.4 years, 194 subjects received a single course of interferon monotherapy, 131 patients developed decompensation (ascites, bleeding, hepatic encephalopathy), 109 patients had hepatocellular carcinoma (HCC), 9 had liver transplant, and 158 died. Esophageal varices were associated with development of decompensation (hazard ratio (HR), 2.09; 95% confidence interval (CI), 1.33-3.30) and liver-related death (HR, 2.27; 95% CI, 1.41-3.66). A MELD score of > 10 predicted overall mortality (HR, 2.15; 95% CI, 1.50-3.09). Overall survival of patients with MELD < or = 10 was 80% at 10 years. HCC occurrence increased the risk of decompensation fivefold (HR, 5.52; 95% CI, 3.77-8.09). Hepatic and overall mortality hazard ratios were 8.62 (95% CI, 5.57-13.3) and 3.80 (95% CI, 2.67-5.42), respectively, for patients who developed HCC, and 16.9 (95% CI, 9.97-28.6) and 7.08 (95% CI, 4.88-10.2) for those who experienced decompensation. CONCLUSIONS: In patients with compensated HCV-induced cirrhosis, the presence of esophageal varices at baseline predicted decompensation and mortality. The development of HCC during follow-up strongly hastens the occurrence of decompensation, which is the main determinant of death. Patients with a MELD score < or = 10 at study entry had a prolonged life expectancy.
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Causas de Morte , Varizes Esofágicas e Gástricas/mortalidade , Hepatite C Crônica/complicações , Cirrose Hepática/patologia , Cirrose Hepática/virologia , Falência Hepática/mortalidade , Adulto , Idoso , Antivirais/uso terapêutico , Biópsia por Agulha Fina , Estudos de Coortes , Intervalos de Confiança , Progressão da Doença , Varizes Esofágicas e Gástricas/etiologia , Varizes Esofágicas e Gástricas/patologia , Feminino , Seguimentos , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/patologia , Humanos , Imuno-Histoquímica , Interferon-alfa/uso terapêutico , Estimativa de Kaplan-Meier , Cirrose Hepática/etiologia , Cirrose Hepática/mortalidade , Falência Hepática/fisiopatologia , Falência Hepática/virologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Probabilidade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Medição de Risco , Índice de Gravidade de Doença , Análise de Sobrevida , Fatores de TempoRESUMO
UNLABELLED: Hepatocellular carcinoma (HCC) is the most frequent cause of death in patients with hepatitis C virus (HCV)-induced cirrhosis. Despite a number of studies in different populations worldwide suggesting an association between HCV genotype 1 and the risk of HCC, no consensus has emerged yet on this matter, which is still controversial. In an attempt to clarify this issue, a prospective study of 163 consecutive HCV-positive patients with cirrhosis, who were enrolled between January 1989 and December 1990, was carried out. HCC occurrence was detected by ultrasound surveillance every 6 months. Independent predictors of HCC were assessed with a Cox regression analysis. After a median follow-up of 10.7 years, 44 [4.26/100/year, confidence interval (CI) = 3.11-5.68/100/year] of 104 patients infected with genotype 1b developed HCC versus 10 (1.69/100/year, CI = 0.82-3.09/100/year) of 52 patients infected with genotype 2a/c (P = 0.0001). Multivariate analysis showed that HCV genotype 1b was independently associated with HCC development [hazard ratio (HR) = 3.02, 95% CI = 1.40-6.53]. Other predictors of HCC were esophageal varices (HR = 2.15, 95% CI = 1.03-4.47), male gender (HR = 2.12, 95% CI = 1.10-4.11), and age over 60 years (HR = 5.96, 95% CI = 1.23-28.8). CONCLUSION: HCV genotype 1b is associated with a statistically significant higher risk of developing HCC. Patients with cirrhosis that are infected with this genotype require more intensive surveillance for the early detection and aggressive management of neoplasia.
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Carcinoma Hepatocelular/virologia , Hepacivirus/genética , Cirrose Hepática/virologia , Neoplasias Hepáticas/virologia , Feminino , Genótipo , Hepatite C Crônica/complicações , Hepatite C Crônica/virologia , Humanos , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de RiscoRESUMO
BACKGROUND: No information is available on the hepatic and extrahepatic pathways of bile acid synthesis in normal children and in pediatric cholestatic liver diseases. METHODS: To explore the changes of the two pathways of bile acid synthesis during development, plasma concentrations of 7alpha-hydroxycholesterol and 27-hydroxycholesterol were measured in 50 healthy children (1 month-14 years) and compared to 18 adult controls. We also measured plasma oxysterols in 31 patients with pediatric cholestatic liver disease. RESULTS: A progressive increase of plasma concentrations of both 27-hydroxycholesterol and 7alpha-hydroxycholesterol was found with age. In children with cystic fibrosis-associated liver disease plasma concentrations of 27-hydroxycholesterol were significantly lower compared to age-matched controls (5.6+/-0.5 vs. 12.8+/-1.1 microg/dl; p<0.001) and paralleled significantly lower concentrations of total cholesterol. In infants with biliary atresia plasma concentrations of 27-hydroxycholesterol were significantly higher compared to age-matched controls (8.8+/-0.8 vs. 4.4+/-0.6 microg/dl, p<0.001) paralleling significantly higher concentrations of total cholesterol while 7alpha-hydroxycholesterol resulted significantly lower (1.2+/-0.2 vs. 2.3+/-0.3 microg/100 mg of total cholesterol; p=0.011). CONCLUSIONS: Our data suggest that both pathways of bile acid synthesis reach a state of maturity only after the age of 4 years and are significantly influenced also in children by liver function and intestinal absorption of cholesterol.
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Ácidos e Sais Biliares/biossíntese , Colestase/sangue , Colesterol/sangue , Hidroxicolesteróis/sangue , Adolescente , Adulto , Criança , Pré-Escolar , Colesterol/metabolismo , Doença Crônica , Feminino , Humanos , Hidroxicolesteróis/metabolismo , Lactente , MasculinoRESUMO
Primary biliary cirrhosis (PBC), which is characterised by progressive destruction of intrahepatic bile ducts, is not a rare disease since both prevalence and incidence are increasing during the last years mainly due to the improvement of case finding strategies. The prognosis of the disease has improved due to both the recognition of earlier and indolent cases, and to the wide use of ursodeoxycholic acid (UDCA). New indicators of prognosis are available that will be useful especially for the growing number of patients with less severe disease. Most patients are asymptomatic at presentation. Pruritus may represent the most distressing symptom and, when UDCA is ineffective, cholestyramine represents the mainstay of treatment. Complications of long-standing cholestasis may be clinically relevant only in very advanced stages. Available data on the effects of UDCA on clinically relevant end points clearly indicate that the drug is able to slow but not to halt the progression of the disease while, in advanced stages, the only therapeutic option remains liver transplantation.
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Doenças Autoimunes/complicações , Doenças Autoimunes/terapia , Colagogos e Coleréticos/uso terapêutico , Cirrose Hepática Biliar/complicações , Cirrose Hepática Biliar/terapia , Transplante de Fígado , Animais , Doenças Autoimunes/epidemiologia , Doenças Autoimunes/patologia , Doenças Ósseas Metabólicas/etiologia , Doenças Ósseas Metabólicas/terapia , Resina de Colestiramina/uso terapêutico , Progressão da Doença , Fadiga/etiologia , Fadiga/terapia , Humanos , Hiperlipidemias/etiologia , Hiperlipidemias/terapia , Hipertensão Portal/etiologia , Hipertensão Portal/terapia , Cirrose Hepática Biliar/epidemiologia , Cirrose Hepática Biliar/patologia , Desnutrição/etiologia , Desnutrição/terapia , Prurido/etiologia , Prurido/terapia , Fatores de Risco , Resultado do Tratamento , Ácido Ursodesoxicólico/uso terapêuticoRESUMO
BACKGROUND: Cholesterol elimination occurs through bile acid synthesis that starts within the liver from 7alpha-hydroxylation or in extrahepatic tissues from 27-hydroxylation. This study was aimed at investigating in vivo these two pathways in patients with chronic liver disease. METHODS: Serum concentrations of 7alpha- and 27-hydroxycholesterol were measured in 54 patients (29 with primary biliary cirrhosis and 25 with chronic hepatitis C) and 18 controls. The rate of oxysterol plasma appearance was calculated after intravenous infusions of deuterated 7alpha- and 27-hydroxycholesterol in patients (n=8) and control subjects (n=8) who gave consent. The expression of sterol 27-hydroxylase was evaluated in macrophages isolated from 20 subjects. RESULTS: In patients with liver disease, the rate of plasma appearance of 7alpha-hydroxycholesterol was significantly reduced (1.44+/-0.96 vs. 2.75+/-1.43 mg/hour, p=0.03), the degree of reduction being related with the severity of the disease (p=0.01) whereas that of 27-hydroxycholesterol was unaffected. The rate of plasma appearance of 27-hydroxycholesterol was significantly related to its serum concentrations (r=0.54, p=0.03) and to its release from cultured macrophages ( r=0.85, p=0.03). CONCLUSIONS: In liver disease 7alpha-hydroxylation of cholesterol seems to be impaired while 27-hydroxylation is unaffected. Serum concentrations of 27-hydroxycholesterol are useful to obtain information on the activity of this alternative pathway.
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Ácidos e Sais Biliares/biossíntese , Hepatite Crônica/fisiopatologia , Hidroxicolesteróis/metabolismo , Cirrose Hepática Biliar/fisiopatologia , Macrófagos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Ácidos e Sais Biliares/metabolismo , Vias Biossintéticas/fisiologia , Estudos de Casos e Controles , Células Cultivadas , Colestanotriol 26-Mono-Oxigenase/genética , Colestanotriol 26-Mono-Oxigenase/metabolismo , Feminino , Humanos , Hidroxicolesteróis/sangue , Hidroxilação , Masculino , Pessoa de Meia-IdadeRESUMO
Primary biliary cirrhosis (PBC) is a chronic liver disease characterized by severe intraepatic cholestasis. Pruritus often occurs during the course of the illness. We designed a study aimed at assessing whether pruritus is associated with dysfunction of signal transduction. Seventeen female patients affected by PBC were enrolled into the study and divided in two groups according to severity of liver disease. Leukocytes were isolated from peripheral blood and Gi, Go and Gs protein expressions were evaluated by western blotting, while G protein function was assessed by measuring cyclic adenosine phosphate formation. The expression of all types of G proteins was increased in leukocytes of PBC patients. The basal adenylate activity was significally higher than control in patients with less severe liver disease, while it was lower than normal in those with severe liver disease. Incubation of patient leukocytes with guanosine triphosphate-gamma-S and Gs protein activators failed to enhance cAMP production, while N-formyl-met-leu-phe was more effective in reducing cAMP production. The expression of all G proteins was non-selectively increased in PBC leukocytes, while adenylate cyclase activity was significantly modified. However, the observed changes in G proteins expression and in adenylate cyclase activity are not related to the presence of pruritus.
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Hepatitis C virus (HCV) has a high propensity to establish chronic infections. Failure of HCV-infected individuals to activate effective antiviral immune responses is at least in part related to HCV-induced impairment of dendritic cells (DCs) that play a central role in activating T cell responses. Although the impact of HCV on DC phenotype and function is likely to be more prominent in the liver, major HCV-induced alterations are detectable in peripheral blood DCs (pbDCs) that represent the most accessible source of DCs. These alterations include numerical reduction, impaired production of inflammatory cytokines and increased production of immunosuppressive IL10. These changes in DCs are relevant to our understanding the immune mechanisms underlying the propensity of HCV to establish persistent infection. Importantly, the non-invasive accessibility of pbDCs renders the analysis of these cells a convenient procedure that can be serially repeated in patient follow-up. Accordingly, the study of pbDCs in HCV-infected patients during conventional treatment with pegylated interferon and ribavirin indicated that restoration of normal plasmacytoid DC count may represent an additional mechanism contributing to the efficacy of the dual therapy. It also identified the pre-treatment levels of plasmacytoid DCs and IL10 as putative predictors of response to therapy. Treatment of chronic HCV infection is changing, as new generation direct-acting antiviral agents will soon be available for use in interferon-free therapeutic strategies. The phenotypic and functional analysis of pbDCs in this novel therapeutic setting will provide a valuable tool for investigating mechanisms underlying treatment efficacy and for identifying predictors of treatment response.
Assuntos
Antivirais/uso terapêutico , Células Dendríticas/efeitos dos fármacos , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Células Dendríticas/imunologia , Células Dendríticas/virologia , Quimioterapia Combinada , Hepacivirus/imunologia , Hepacivirus/patogenicidade , Hepatite C Crônica/sangue , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/imunologia , Interações Hospedeiro-Patógeno , Humanos , Ativação Linfocitária/efeitos dos fármacos , Fenótipo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/virologia , Resultado do TratamentoRESUMO
BACKGROUND: The ABCB4 gene encodes the MDR3 protein. Mutations of this gene cause progressive familial intrahepatic cholestasis type 3 (PFIC3) in children, but their clinical relevance in adults remains ill defined. The study of a well-characterized adult patient series may contribute to refining the genetic data regarding cholangiopathies of unknown origin. Our aim was to evaluate the impact of ABCB4 mutations on clinical expression of cholestasis in adult patients. METHODS: We consecutively evaluated 2602 subjects with hepatobiliary disease. Biochemical evidence of a chronic cholestatic profile (CCP) with elevated serum gamma-glutamyltransferase activity or diagnosis of intrahepatic cholestasis of pregnancy (ICP) and juvenile cholelithiasis (JC) were inclusion criteria. The personal/family history of additional cholestatic liver disease (PFH-CLD), which includes ICP, JC, or hormone-induced cholestasis, was investigated. Mutation screening of ABCB4 was carried out in 90 patients with idiopathic chronic cholestasis (ICC), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), ICP, and JC. RESULTS: Eighty patients had CCP. PSC and ICC patients with PFH-CLD had earlier onset of disease than those without it (p = 0.003 and p = 0.023, respectively). The mutation frequency ranged from 50% (ICP, JC) to 17.6% (PBC). Among CCP patients, presence or absence of PFH-CLD was associated with ABCB4 mutations in 26.8 vs 5.1% (p = 0.013), respectively; in the subset of ICC and PSC patients, the corresponding figures were 44.4 vs 0% (p = 0.012) and 28.6 vs 8.7% (p = 0.173). CONCLUSIONS: Cholangiopathies attributable to highly penetrant ABCB4 mutant alleles are identifiable in a substantial proportion of adults that generally have PFH-CLD. In PSC and ICC phenotypes, patients with MDR3 deficiency have early onset of disease.
Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Colestase/genética , Mutação , Subfamília B de Transportador de Cassetes de Ligação de ATP/deficiência , Adolescente , Adulto , Idade de Início , Idoso , Sequência de Aminoácidos , Estudos de Casos e Controles , Criança , Colangite Esclerosante/genética , Colestase Intra-Hepática/genética , Doença Crônica , Feminino , Humanos , Cirrose Hepática Biliar/genética , Masculino , Pessoa de Meia-Idade , Fenótipo , Complicações na Gravidez/genética , Alinhamento de Sequência , Adulto JovemRESUMO
BACKGROUND: Bile acid synthesis accounts for more than 95% of total cholesterol catabolism per day. We have developed a minimally invasive technique in humans that quantifies the rates of plasma appearance of 7alpha- and 27-hydroxycholesterol, representing the first steps of the "classical" and "alternative" pathways of bile acid synthesis, respectively. METHODS: For this purpose, during the intravenous infusion of synthetic deuterated isotopomers of 7alpha-hydroxycholesterol and 27-hydroxycholesterol plasma samples are collected and analysed by a GC-MS based method that allows to quantify the exogenous/natural isotopomer ratio of the two sterols. From this data, the rates of plasma appearance of 7alpha- and 27-hydroxycholesterol are calculated. RESULTS: In a group of healthy individuals steady state kinetics are obtained during a 2 h period yielding mean values of 2.0+/-0.8 and 3.7+/-0.6 mg/h for 7alpha- and 27-hydroxycholesterol, respectively. The data are consistent with findings using older techniques that require studies over several days. CONCLUSION: Considering that at steady state of the exogenous/natural isotopomer ratio the plasma appearance of the two regulatory hydroxysterols are related to the rate of bile acid synthesis via the "classical" and the "alternative" pathways, respectively, the proposed method could be used to evaluate the immediate effects of different diets and drugs and other determinants on cholesterol catabolism.
Assuntos
Ácidos e Sais Biliares/biossíntese , Hidroxicolesteróis/metabolismo , Adulto , Deutério , Feminino , Humanos , Fígado/enzimologia , MasculinoRESUMO
BACKGROUND: Interferon Lambda-3 (IFN-λ3) gene polymorphism is associated with spontaneous clearance of hepatitis C virus (HCV) and response to IFN-based therapy (IFN). However, very few data are available about its value in predicting sustained virologic response (SVR) in patients with cirrhosis, and whether IFN-λ3 genotype influences liver disease progression remains unclear. METHODS: We determined IFN-λ3 genotype by PCR in a cohort of patients with compensated HCV-related cirrhosis, enrolled between 1989 and 1992. Person-years follow-up was calculated for each individual from the date of enrolment to the development of first episode of decompensation, HCC, liver transplant, death or end of follow-up. The follow-up of patients who achieved SVR was censored at the time of IFN initiation. Kaplan-Meier curves and Cox regression analyses were used to assess the association between IFN-λ3 genotype and clinical outcome. RESULTS: IFN-λ3 was determined in 264 patients (52% males, mean age 57±8 years, 67% HCV genotype (G)1, while CC, CT and TT genotypes were 36%, 50% and 14%, respectively. During a median follow-up of 14.8 years, 149 (56%) patients received IFN. Overall, SVR was achieved in 31 (21%) patients, 40% among those with CC genotype (22% in G1 and 61% in G2, respectively) compared to 10% and 13% among patients with CT and TT genotypes (p<0.0001). Univariate and multivariate analyses found no association between IFN-λ3 (CC vs. non-CC genotype) and disease progression. CONCLUSION: IFN-λ3 determination is fundamental for allocating cirrhotic patients to be treated with IFN, while it has no value in predicting the outcome of the disease.
Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Interferons/uso terapêutico , Interleucinas/genética , Cirrose Hepática/tratamento farmacológico , Idoso , Estudos de Coortes , Progressão da Doença , Feminino , Genótipo , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/genética , Hepatite C Crônica/mortalidade , Humanos , Cirrose Hepática/genética , Cirrose Hepática/virologia , Transplante de Fígado , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Resultado do TratamentoRESUMO
T-cell receptor (TCR) plays a key role in immune regulation and polymorphisms of its genes have been found in association with several autoimmune diseases. No data are available for primary biliary cirrhosis, an autoimmune liver disease the natural history of which is highly variable. We studied a TCR constant beta-2 chain polymorphism in 70 patients affected by primary biliary cirrhosis and in 70 healthy controls. The DNA chains of patients and controls were amplified by means of polymerase chain reaction using primers designed around a Bgl II polymorphic restriction site and digested for restriction fragment length polymorphism analysis. We found a slight increase of the heterozygous genotype in patients compared with controls (49 vs 40%), which became higher if only patients with early disease were considered (60 vs 40%). Heterozygous patients had less severe disease as indicated by a lower Mayo score (5.1 +/- 1.2 vs 5.7 +/- 1.2 in non-heterozygous). Our data suggest that TCR constant beta-2 polymorphism does not play a key role in modulating the multifactorial etiopathogenesis of primary biliary cirrhosis.