RESUMO
BACKGROUND: The relationships between primary sclerosing cholangitis (PSC) and the environment are largely unknown. AIM: To validate associations reported in previous studies and to identify novel environmental exposures among PSC patients. METHODS: We performed a multicenter, case-control analysis utilising self-administered questionnaires. Responses between cases (n = 1000) and controls (n = 663) were compared using multivariable logistic regression adjusted for age and gender. The model was further stratified based on inflammatory bowel disease (IBD) status (with IBD n = 741 without IBD n = 259). RESULTS: Smoking was associated with PSC only when IBD was present (OR, 0.5; 95% CI 0.4-0.7) but not among those PSC patients without IBD (OR, 0.9; 95% CI 0.7-1.2). Compared to controls, women with PSC (irrespective of the presence of IBD) were less likely to have received hormone replacement therapy (HRT; OR, 0.5; 95% CI 0.4-0.7) and were more likely to have recurrent urinary tract infections (OR, 1.6; 95% CI 1.2-2.3). PSC patients regardless of gender or IBD status were less likely to eat fish (OR, 0.4; 95% CI 0.3-0.6) and grilled/barbecued meat (OR, 0.8; 95% CI 0.7-0.9). In contrast, PSC patients with and without IBD were more likely to consume steak/burgers that were more well done (OR, 1.3; 95% CI 1.2-1.5). CONCLUSIONS: IBD (rather than PSC) is associated with smoking. Women with PSC are more likely to have recurrent urinary tract infections and less likely to receive HRT. Dietary intake and methods of food preparation differ in PSC patients when compared to controls.
Assuntos
Colangite Esclerosante/epidemiologia , Exposição Ambiental/efeitos adversos , Doenças Inflamatórias Intestinais/epidemiologia , Fumar/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Canadá/epidemiologia , Estudos de Casos e Controles , Criança , Colangite Esclerosante/etiologia , Feminino , Humanos , Doenças Inflamatórias Intestinais/etiologia , Masculino , Pessoa de Meia-Idade , Fumar/epidemiologia , Inquéritos e Questionários , Estados Unidos/epidemiologia , Adulto JovemRESUMO
We fine mapped two primary biliary cirrhosis (PBC) risk loci, CLEC16A (C-type lectin domain family 16 member A)-suppressor of cytokine signaling 1 (SOCS1) and Spi-B protein (SPIB) and sequenced a locus, sialic acid acetylesterase (SIAE), proposed to harbor autoimmunity-associated mutations. In all, 1450 PBC cases and 2957 healthy controls were genotyped for 84 single-nucleotide polymorphisms (SNPs) across the CLEC16A-SOCS1 and SPIB loci. All 10 exons of the SIAE gene were resequenced in 381 cases and point substitutions of unknown significance assayed for activity and secretion. Fine mapping identified 26 SNPs across the CLEC16A-SOCS1 and 11 SNPs across the SPIB locus with significant association to PBC, the strongest signals at the CLEC16A-SOCS1 locus emanating from a SOCS1 intergenic SNP (rs243325; P=9.91 × 10(-9)) and at the SPIB locus from a SPIB intronic SNP (rs34944112; P=3.65 × 10(-9)). Among the associated SNPs at the CLEC16A-SOCS1 locus, two within the CLEC16A gene as well as one SOCS1 SNP (rs243325) remained significant after conditional logistic regression and contributed independently to risk. Sequencing of the SIAE gene and functional assays of newly identified variants revealed six patients with functional non-synonymous SIAE mutations (Fisher's P=9 × 10(-4) vs controls) We demonstrate independent effects on risk of PBC for CLEC16A, SOCS1 and SPIB variants, while identifying functionally defective SIAE variants as potential factors in risk for PBC.
Assuntos
Acetilesterase/genética , Proteínas de Ligação a DNA/genética , Lectinas Tipo C/genética , Cirrose Hepática Biliar/genética , Proteínas de Transporte de Monossacarídeos/genética , Proteínas Supressoras da Sinalização de Citocina/genética , Fatores de Transcrição/genética , Acetilesterase/metabolismo , Alelos , Estudos de Casos e Controles , Mapeamento Cromossômico/métodos , Proteínas de Ligação a DNA/metabolismo , Ensaios Enzimáticos , Loci Gênicos , Predisposição Genética para Doença , Haplótipos , Humanos , Lectinas Tipo C/metabolismo , Cirrose Hepática Biliar/imunologia , Cirrose Hepática Biliar/metabolismo , Modelos Logísticos , Proteínas de Transporte de Monossacarídeos/metabolismo , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Proteína 1 Supressora da Sinalização de Citocina , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Fatores de Transcrição/metabolismoRESUMO
BACKGROUND: Ursodeoxycholic acid (UDCA) in a dose of 28-30 mg/kg/day increases the likelihood of clinical deterioration of primary sclerosing cholangitis (PSC) patients. AIM: To compare the risk of adverse clinical endpoints in patients with varying disease status. METHODS: We reviewed records from patients previously enrolled in a study evaluating the effects of high dose (28-30 mg/kg/day) UDCA in PSC. Patients were grouped according to treatment (UDCA vs. placebo) and baseline disease status (histological stage of PSC, total serum bilirubin). Development of clinical endpoints including death, liver transplantation, cirrhosis, oesophageal varices and cholangiocarcinoma was sought. RESULTS: A total of 150 patients were included of whom 49 patients developed endpoints. There was an increased development of endpoints among patients using UDCA vs. placebo (14 vs. 4, P=0.0151) with early histological disease (stage 1-2, n=88) but not with late stage (stage 3-4, n=62) disease (17 vs. 14, P=0.2031). Occurrence of clinical endpoints was also higher in patients receiving UDCA vs. placebo (16 vs. 2, P=0.0008) with normal bilirubin levels (total bilirubin ≤1.0 mg/dL) but not in patients with elevated bilirubin levels (15 vs. 16, P=0.6018). Among patients not reaching endpoints 31.7% had normalisation of their alkaline phosphatase levels when compared to 14.3% in patients who reached endpoints (P=0.073). CONCLUSION: The increased risk of adverse events with UDCA treatment when compared with placebo is only apparent in patients with early histological stage disease or normal total bilirubin.
Assuntos
Bilirrubina/metabolismo , Colagogos e Coleréticos/efeitos adversos , Colangite Esclerosante/tratamento farmacológico , Ácido Ursodesoxicólico/efeitos adversos , Adulto , Colagogos e Coleréticos/administração & dosagem , Colangite Esclerosante/sangue , Relação Dose-Resposta a Droga , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Ácido Ursodesoxicólico/administração & dosagemRESUMO
The availability of hepatitis B immune globulin (HBIG) and several oral antiviral therapies has reduced but not eliminated hepatitis B virus (HBV) recurrence. We aimed to determine the rate of HBV recurrence after orthotopic liver transplantation (OLT) in relation to virologic breakthrough pre-OLT and HBIG regimens post-OLT. Data from the NIH HBV-OLT database were analyzed. A total of 183 patients transplanted between 2001 and 2007 followed for a median of 42 months (range 1-81) post-OLT were studied. At transplant, 29% were hepatitis B e antigen (HBeAg) (+), 38.5% had HBV DNA > 5 log(10) copies/mL, 74% were receiving antiviral therapy. Twenty-five patients experienced virologic breakthrough before OLT. Post-OLT, 26%, 22%, 40% and 12% of patients received intravenous (IV) high-dose, IV low-dose, intramuscular low-dose and a finite duration of HBIG, respectively as maintenance prophylaxis. All but two patients also received antiviral therapy. Cumulative rates of HBV recurrence at 1 and 5 years were 3% and 9%, respectively. Multivariate analysis showed that listing HBeAg status and HBV DNA level at OLT were the only factors associated with HBV recurrence. In conclusion, low rates of HBV recurrence can be accomplished with all the HBIG regimens used when combined with antiviral therapy including patients with breakthrough pre-OLT as long as rescue therapy is administered pre- and post-OLT.
Assuntos
Hepatite B/tratamento farmacológico , Imunoglobulinas/uso terapêutico , Transplante de Fígado/efeitos adversos , Adolescente , Adulto , DNA Viral/análise , Feminino , Hepatite B/prevenção & controle , Antígenos E da Hepatite B/imunologia , Humanos , Imunoglobulinas/administração & dosagem , Transplante de Fígado/imunologia , Masculino , Pessoa de Meia-Idade , Prevenção SecundáriaRESUMO
Both HCV and HIV are common in haemophiliacs previously treated with non-viral-inactivated clotting factor concentrates. Because of increased bleeding risks, little data are available on the safety of percutaneous outpatient liver biopsy (LBx) and impact of HIV coinfection in this population. This study aims at reporting our experience with percutaneous LBx in a cohort of haemophiliacs infected with HCV and describe the spectrum of disease and impact of HIV coinfection. A retrospective review of consecutive patients with haemophilia and HCV who underwent percutaneous LBx was performed. All patients were positive for HCV RNA by commercial assay and received factor concentrate prior to biopsy. A total of 29 male patients (mean age 36, 24 haemophilia A, five haemophilia B, and 44% coinfected with HIV) underwent successful outpatient percutaneous LBx without bleeding complication. Histologic activity index was 6.44 with advanced fibrosis (bridging fibrosis/cirrhosis) in 31%. When patients were stratified by HIV positive (n = 13) vs. HIV negative (n = 16), coinfected patients had higher fibrosis scores and higher proportion advanced fibrosis (54% vs. 12%; P = 0.0167) with no differences in age, demographic or other laboratory parameters. Multivariate logistic regression found that HIV positivity was independently associated with advanced fibrosis (OR = 3.7; 95% CI: 1.17-11.8; P = 0.026). Outpatient percutaneous LBx can be safely performed in patients with haemophilia. Despite similar age, HIV coinfection was an independent predictor of advanced fibrosis. These data support the hypothesis that HIV accelerates fibrosis progression in those coinfected with HCV and highlights the importance of liver histology in this population.
Assuntos
Infecções por HIV/complicações , Hemofilia A/patologia , Hepatite C Crônica/complicações , Fígado/patologia , Adulto , Assistência Ambulatorial , Biópsia/métodos , Infecções por HIV/patologia , Hemofilia A/complicações , Hemofilia A/terapia , Hepatite C Crônica/patologia , Humanos , Masculino , Estudos RetrospectivosRESUMO
BACKGROUND: Ursodeoxycholic acid has been ineffective in the treatment of primary sclerosing cholangitis. Because the pathogenesis of primary sclerosing cholangitis is related to immune destruction of bile duct epithelium, several immune suppressive agents have been evaluated. Mycophenolate mofetil is a potent immunosuppressant that is now widely used in organ transplantation. AIM: In this pilot study to determine if mycophenolate mofetil when combined with ursodeoxycholic acid could prevent evidence of clinical progression and improve the biochemical, histological and/or cholangiographic features of primary sclerosing cholangitis compared with patients treated with ursodeoxycholic acid alone. METHODS: Twenty-five patients with well-defined primary sclerosing cholangitis were randomized to ursodeoxycholic acid (13-15 mg/kg/day) with or without mycophenolate mofetil (1000 mg b.d.). Cholangiography and liver biopsy were performed at study entry and after 2 years of treatment. Symptoms, clinical features of liver disease and biochemical tests were monitored at 3-month intervals. RESULTS: The mean age 44 years, 58% male, 84% Caucasian and 64% had ulcerative colitis. After 2 years, there were no differences in laboratory values, histological stage or cholangiograms between patients treated with ursodeoxycholic acid alone and those treated with mycophenolate mofetil + ursodeoxycholic acid. CONCLUSIONS: Mycophenolate mofetil combined with ursodeoxycholic acid does not appear to provide additional benefit compared with standard doses of ursodeoxycholic acid alone in the treatment of primary sclerosing cholangitis.
Assuntos
Colagogos e Coleréticos/uso terapêutico , Colangite Esclerosante/tratamento farmacológico , Imunossupressores/uso terapêutico , Fígado/patologia , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/uso terapêutico , Ácido Ursodesoxicólico/uso terapêutico , Adulto , Biópsia/métodos , Colangite Esclerosante/patologia , Feminino , Humanos , Masculino , Projetos Piloto , Estudos ProspectivosRESUMO
Each variceal bleed is associated with 20% to 30% risk of dying. Management of portal hypertension after a bleed consists of (1) control of bleeding and (2) prevention of rebleeding. Effective control of bleeding can be achieved either pharmacologically by administering somatostatin or octreotide or endoscopically via sclerotherapy or variceal band ligation. In practice, both pharmacologic and endoscopic therapy are used concomitantly. Rebleeding can be prevented by endoscopic obliteration of varices. In this setting, variceal ligation is the preferred endoscopic modality. B-blockade is as effective as endoscopic therapy and, in combination, the two modalities may be additive.
Assuntos
Hemorragia/etiologia , Hipertensão Portal/complicações , Hipertensão Portal/terapia , Varizes/etiologia , Antagonistas Adrenérgicos beta/uso terapêutico , Cateterismo , Endoscopia , Hemodinâmica , Hemorragia/fisiopatologia , Hemorragia/prevenção & controle , Hemorragia/terapia , Humanos , Ligadura , Nitratos/uso terapêutico , Escleroterapia , Vasodilatadores/uso terapêuticoRESUMO
This study assessed the use of ribavirin monotherapy to enhance sustained virologic response in hepatitis C virus (HCV)-infected patients who achieved virologic response to interferon (IFN)-ribavirin combination therapy. Patients who had chronic HCV infection and prior relapse were retreated with IFN-ribavirin for 6 months. Patients with an end-of-treatment virologic response were assigned randomly to either stop use of both IFN and ribavirin or to continue use of ribavirin as monotherapy for an additional 6 months. HCV RNA became undetectable during treatment in 46 patients, who then entered the randomized trial. Sustained virologic response was observed in 13 of 26 patients who continued ribavirin monotherapy and in 15 of 20 patients who stopped use of both IFN and ribavirin (P, not significant). Sustained virologic response was significantly more common in patients with HCV genotype non-1 (75% vs. 56%) and in patients with a virus titer < 2 x 10(6) copies/mL (93% vs. 43%). The results indicate that continuing ribavirin monotherapy after achieving a virologic response does not improve sustained virologic response.
Assuntos
Antivirais/uso terapêutico , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Interferon Tipo I/uso terapêutico , Ribavirina/uso terapêutico , Adulto , Quimioterapia Combinada , Feminino , Hepacivirus/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Proteínas Recombinantes , Prevenção Secundária , Resultado do TratamentoRESUMO
Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease that predominantly affects middle-aged women; fatigue and pruritus are the most common symptoms at presentation. Liver function tests are consistent with cholestasis and reveal an elevation of serum alkaline phosphatase and gamma-glutamyl transpeptidase with or without elevation of aminotransferase levels. Histologically, PBC is characterized by the destruction of the intrahepatic small bile ducts and subsequently fibrosis. The serological hallmark of the disease is the presence of antimitochondrial antibodies, which are found in 95% of patients with PBC. The antimitochondrial antibodies are directed against the 2-oxo-acid dehydrogenase complexes located on the inner membrane of the mitochondria. PBC generally slowly progresses, even over decades, and may lead to liver failure. In symptomatic patients, advanced age, elevated serum bilirubin levels, decreased serum albumin levels, and cirrhosis each correlate with shortened survival. Immunosuppressive and anti-inflammatory drugs have been used in the treatment of PBC based on the presumed autoimmune pathogenesis, but satisfactory agents leading to complete reversal or cure of the disease are not available. At present ursodeoxycholic acid appears to be the only effective therapy in preventing or delaying the need for liver transplantation and improving survival. However, a number of patients receiving ursodeoxycholic acid still develop progressive disease and require transplantation; transplantation is the only effective therapy at the end stage of the disease.
Assuntos
Cirrose Hepática Biliar/diagnóstico , Síndrome de Sjogren/diagnóstico , Adulto , Feminino , Humanos , Cirrose Hepática Biliar/sangue , Cirrose Hepática Biliar/complicações , Cirrose Hepática Biliar/imunologia , Testes de Função Hepática , Transplante de Fígado , Síndrome de Sjogren/sangue , Síndrome de Sjogren/complicaçõesRESUMO
Many subjects with cryptogenic cirrhosis have underlying nonalcoholic steatohepatitis (NASH). The natural history of NASH-related cryptogenic cirrhosis after orthotopic liver transplantation (OLT) is not well defined. A primarily retrospective study of patients with the clinical histological phenotype of NASH-related cirrhosis undergoing OLT was performed. Data were compared with 2 sets of age- and weight-matched controls with (1) primary biliary cirrhosis or primary sclerosing cholangitis or (2) alcoholic liver disease. After OLT, all patients were managed by a standard immunosuppressive protocol. Liver biopsies were performed at 6 and 12 months after OLT and at 1- to 2-year intervals thereafter, as well as when liver enzyme levels were elevated enough to warrant diagnostic biopsy. Twenty-seven subjects with cryptogenic cirrhosis and a clinical histological phenotype of NASH and 3 patients with a long-standing diagnosis of NASH before OLT were included. The 30-day perioperative mortality was 1 in 30 patients. During a median follow-up of 3.5 +/- 2.7 years, 2 additional patients died of sepsis. There was a time-dependent increase in the risk for allograft steatosis that approached 100% by 5 years compared with only an approximately 25% incidence of steatosis in the control groups (P <.009, log-rank test). On multivariate analysis, only the cumulative steroid dose correlated with time to development of allograft steatosis. Three patients developed histological progression from hepatic steatosis to steatohepatitis. Of these, 1 patient developed progressive fibrosis. Four patients experienced at least 1 episode of acute cellular rejection; however, no patient developed chronic rejection or graft failure. In conclusion, nonalcoholic fatty liver disease occurs frequently after OLT in patients with the phenotype of NASH-related cirrhosis. Despite the frequent histological recurrence of disease, clinical outcomes are similar to those of other groups of patients undergoing OLT.
Assuntos
Fígado Gorduroso/etiologia , Cirrose Hepática/cirurgia , Transplante de Fígado , Complicações Pós-Operatórias , Adulto , Progressão da Doença , Fígado Gorduroso/patologia , Feminino , Humanos , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
BACKGROUND AND AIMS: The pathogenesis of nonalcoholic steatohepatitis (NASH) is unknown. We tested the hypothesis that NASH is associated with 2 defects: (1) peripheral insulin resistance, which increases lipolysis, delivery of free fatty acids (FFA) to the liver, and hepatic fatty acid beta oxidation, thereby creating oxidative stress; and (2) an abnormality within the hepatocytes that might render them more susceptible to injury from oxidative stress. METHODS: The hypothesis was tested by evaluation of (1) insulin resistance by a 2-step hyperinsulinemic (10 and 40 mU. m(-2). min(-1)) euglycemic clamp; (2) insulin effects on lipolysis by enrichment of [U-(13)C]glycerol; (3) frequency and severity of structural defects in hepatocyte mitochondria in vivo; (4) fatty acid beta oxidation from serum [beta-OH butyrate], release of water-soluble radioactivity from (3)H-palmitate by cultured fibroblasts and urinary dicarboxylic acid excretion; and (5) hepatic lipid peroxidation by immunohistochemical staining for 3-nitrotyrosine (3-NT). Subjects with NASH (n = 6-10 for different studies) were compared with those with fatty liver (n = 6) or normal controls (n = 6). RESULTS: NASH and fatty liver were both associated with insulin resistance, with mean glucose infusion rates (normal/fatty liver/NASH) of step 1, 4.5/1.6/0.9; step 2, 9.5/7.7/4.5 (P < 0.03 for both steps). Although baseline rates of glycerol appearance were higher in those with NASH than in those with fatty liver (means, 14.6 vs. 21.6 micromol. kg(-1). min(-1); P < 0.05), neither group significantly suppressed glycerol appearance at insulin infusion rates of 10 mU. m(-2). min(-1). NASH was associated with loss of mitochondrial cristae and paracrystalline inclusions in 9 of 10 subjects, compared with 0 of 6 subjects with fatty liver. However, no evidence of a generalized defect in fatty acid beta oxidation was noted in any group. Also, mean [beta-OH butyrate] was highest in those with NASH (means, 90 vs. 110 vs. 160 micromol/L; P < 0.04). Increased staining for 3-NT was present in fatty liver, and even greater staining was seen in NASH. CONCLUSIONS: These data indicate that peripheral insulin resistance, increased fatty acid beta oxidation, and hepatic oxidative stress are present in both fatty liver and NASH, but NASH alone is associated with mitochondrial structural defects.
Assuntos
Fígado Gorduroso/metabolismo , Resistência à Insulina , Mitocôndrias Hepáticas/patologia , Adulto , Idoso , Biópsia , Células Cultivadas , Ácidos Dicarboxílicos/urina , Ácidos Graxos não Esterificados/sangue , Fígado Gorduroso/patologia , Feminino , Fibroblastos/citologia , Técnica Clamp de Glucose , Glicerol/sangue , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Hiperinsulinismo/metabolismo , Hiperinsulinismo/patologia , Insulina/sangue , Peroxidação de Lipídeos , Lipólise , Masculino , Pessoa de Meia-Idade , Mitocôndrias Hepáticas/metabolismo , Palmitatos/farmacologia , TrítioRESUMO
Bleeding esophageal varices, one of the most feared complications of portal hypertension, contribute to the estimated 32,000 deaths annually attributed to cirrhosis. Successful control requires knowledge of the pertinent anatomy, underlying pathophysiology of portal hypertension, and natural history of gastro-esophageal varices. Drs Hegab and Luketic review these topics and discuss the various prophylactic and therapeutic approaches to management, including pharmacologic agents, endoscopic sclerotherapy, and trans-jugular intrahepatic portosystemic shunt (TIPS).
Assuntos
Varizes Esofágicas e Gástricas , Hemorragia Gastrointestinal , Cirrose Hepática/complicações , Algoritmos , Varizes Esofágicas e Gástricas/diagnóstico , Varizes Esofágicas e Gástricas/etiologia , Varizes Esofágicas e Gástricas/fisiopatologia , Varizes Esofágicas e Gástricas/terapia , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/fisiopatologia , Hemorragia Gastrointestinal/terapia , Humanos , Hipertensão Portal/complicações , Hipertensão Portal/etiologia , Hipertensão Portal/fisiopatologia , Sistema Porta/anatomia & histologiaRESUMO
Ninety-five patients with chronic hepatitis C virus (HCV) infection, 35 with persistently normal serum alanine aminotransferase (ALT) levels, were randomized to treatment with daily interferon (IFN) for 3 months, followed by IFN 3 times weekly (TIW) for 12 months (group A) or TIW for 18 months (group B). Patients with elevated versus normal ALT levels had similar demographic and virologic characteristics but significantly (P<.05) more advanced liver histology (bridging fibrosis and cirrhosis, 37.9% vs. 11.4%). After 3 months of treatment, 38.3% of patients in group A were HCV RNA negative versus 18.8% in group B (P<.05). When the IFN dose was reduced from daily to TIW in group A, the percentage of patients who remained HCV RNA negative declined; sustained virologic response was similar in both groups (10.6% vs. 8.3%). Response to treatment was similar in patients with elevated or normal ALT levels. Persons with chronic HCV infection and persistently normal serum ALT levels have milder liver disease than, and respond to IFN therapy similarly to, persons with elevated ALT levels.
Assuntos
Alanina Transaminase/sangue , Antivirais/uso terapêutico , Hepatite C Crônica/sangue , Hepatite C Crônica/tratamento farmacológico , Interferons/uso terapêutico , Adulto , Feminino , Fibrose , Hepacivirus/genética , Hepacivirus/isolamento & purificação , Hepatite C Crônica/patologia , Humanos , Fígado/patologia , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Resultado do TratamentoRESUMO
OBJECTIVE: The present study was designed to evaluate the effectiveness of interferon-ribavirin combination therapy for treatment of chronic hepatitis C virus (HCV) in patients who failed previous treatment with interferon monotherapy. METHODS: A total of 140 patients with well-documented chronic HCV who failed to achieve a virological (if HCV-RNA was assessed) or biochemical response (if HCV-RNA was not assessed) to interferon monotherapy, 3 mU three times weekly (TIW) for 3-18 months, were randomly assigned to one of three treatment groups. Group A patients were treated with 5 mU interferon TIW for 6 months. Ribavirin (1000-1200 mg daily) was added in those patients HCV-RNA positive at month 3. Group B patients were treated with 3 mU interferon TIW plus ribavirin (1000-1200 mg daily) for 6 months. The dose of interferon was increased to 5 mU TIW in those patients HCV-RNA positive at month 3. Group C patients were treated with 5 mU interferon TIW plus ribavirin (1000-1200 mg daily) for 6 months. Serum ALT and HCV-RNA were monitored during and after treatment for a total of 15 months. RESULTS: Seventeen percent of patients in group A became HCV-RNA negative by treatment month 3. Adding ribavirin resulted in one additional patient becoming HCV-RNA negative. However, none of the patients in this group achieved sustained virological response. Twenty-six percent of patients in group B became HCV-RNA negative by treatment month 3. Increasing the dose of interferon from 3 to 5 mU TIW increased virological response to 30%. However, sustained virological response was observed in only 14%. Thirty percent of patients in group C became HCV-RNA negative, but sustained virological response was observed in only 12%. Sustained virological response was found to be significantly greater in patients with a nontype I HCV genotype (p < 0.002) and in patients who had a decline in HCV-RNA titer to a value < 100,000 copies/ml during their previous course of interferon monotherapy (p < 0.0001). None of the 12 sustained responders were African Americans (p < 0.013). CONCLUSIONS: Retreatment of nonresponders with interferon-ribavirin combination therapy results in limited benefit; only 13% of patients achieved sustained virological response. Response was extremely poor in African Americans and those with HCV genotype 1.
Assuntos
Antivirais/administração & dosagem , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/administração & dosagem , Ribavirina/administração & dosagem , Adulto , Antivirais/efeitos adversos , Relação Dose-Resposta a Droga , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Interferon alfa-2 , Interferon-alfa/efeitos adversos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes , Ribavirina/efeitos adversos , Falha de TratamentoRESUMO
The last half century has witnessed great advances in the understanding of the pathogenesis and natural history of portal hypertension in cirrhotics. Several pharmacologic and endoscopic techniques have been developed for the treatment of portal hypertension. The use of these agents in a given patient must be based on an understanding of the stage in the natural history of the disease and the relative efficacy and safety of the available treatment options.
Assuntos
Endoscopia do Sistema Digestório , Varizes Esofágicas e Gástricas , Escleroterapia/métodos , Antagonistas Adrenérgicos beta/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Cateterismo , Ensaios Clínicos como Assunto , Quimioterapia Combinada , Varizes Esofágicas e Gástricas/diagnóstico , Varizes Esofágicas e Gástricas/etiologia , Varizes Esofágicas e Gástricas/terapia , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/prevenção & controle , Humanos , Ligadura , Soluções Esclerosantes/uso terapêutico , Resultado do TratamentoRESUMO
The role of surgery in the prevention and treatment of variceal hemorrhage is reviewed. Types of available surgery, their physiologic basis, and literature supporting their use are discussed in the context of the natural history of variceal hemorrhage. The evolution of transjugular intrahepatic portosystemic shunt (TIPS) as a treatment modality for variceal hemorrhage is reviewed. The effects of TIPS on portal and systemic hemodynamics and clinical usefulness in the management of variceal hemorrhage are discussed. A treatment algorithm for the integrated use of the various treatments is provided.
Assuntos
Endoscopia do Sistema Digestório , Varizes Esofágicas e Gástricas/cirurgia , Transplante de Fígado , Derivação Portossistêmica Transjugular Intra-Hepática , Esplenectomia , Varizes Esofágicas e Gástricas/complicações , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/prevenção & controle , Humanos , Prevenção Secundária , Resultado do TratamentoRESUMO
BACKGROUND: The shortage of cadaveric livers has sparked an interest in adult-to-adult living donor transplantation. Right lobe donor hepatectomy is frequently required to obtain a graft of adequate size for adult recipients. Careful donor selection is necessary to minimize complications and assure a functional graft. METHODS: A four-step evaluation protocol was used for donor selection and satisfactory results of all tests in each step were required before proceeding to the next. Donors were selected based on a battery of laboratory studies chosen to exclude unrecognized infection, liver disease, metabolic disorders, and conditions representing undue surgical risk. Imaging studies included ultrasonography, angiography, magnetic resonance imaging, and intraoperative cholangiography and ultrasonography. The information obtained from liver biopsy was used to correct the estimated graft mass for the degree of steatosis. RESULTS: From March 1998 to August 1999, 126 candidates were evaluated for living donation. A total of 35 underwent donor right lobectomy with no significant complications. Forty percent of all donors that came to surgery were genetically unrelated to the recipient. A total of 69% of those evaluated were excluded. ABO incompatibility was the primary reason for exclusion after the first step (71%) and the presence of steatosis yielding an inadequate estimated graft mass after the second step (20%). CONCLUSIONS: Donor selection limits the application of living donor liver transplantation in the adult population. Unrelated individuals increase the size of the donor pool. Right lobe hepatectomy can be performed safely in healthy adult liver donors. Preoperative liver biopsy is an essential part of the evaluation protocol, particularly when the estimated graft mass is marginal.
Assuntos
Transplante de Fígado , Doadores Vivos , Seleção de Pessoal/métodos , Obtenção de Tecidos e Órgãos , Adulto , Biópsia , Seguimentos , Hepatectomia , Humanos , Fígado/patologia , Complicações Pós-OperatóriasRESUMO
BACKGROUND: The high mortality rate associated with fulminant hepatic failure combined with the limited availability of cadaveric organs requires consideration of alternatives to conventional cadaveric transplantation. Use of the donor right lobe in adult-to-adult living donor transplantation holds promise in a variety of circumstances, including high-acuity situations. METHODS: A 28-year-old male with fulminant hepatic failure secondary to hepatitis B was referred to our institution. He rapidly progressed to grade IV encephalopathy, and laboratory values were indicative of a poor prognosis without transplantation. He was listed for transplantation as UNOS status I. Three siblings were simultaneously evaluated for living liver donation. Following established protocols, we completed donor evaluation in less than 24 hr, and donor right lobectomy and living donor transplantation were performed within 36 hr of the recipient's admission to our center. RESULTS: The donor surgery was uncomplicated, and the patient was discharged on postoperative day 4. The recipient experienced full recovery and was discharged home on postoperative day 14. Of note, the first offer for a cadaveric liver came more than 60 hr after living donor transplantation. CONCLUSIONS: Thorough donor workup can be completed in less than 24 hr without inappropriate abbreviation of the evaluation. Simultaneous workup of willing individuals prevents unnecessary delay. Living donor transplantation should be considered for patients with fulminant hepatic failure who are appropriate transplant candidates.
Assuntos
Encefalopatia Hepática/cirurgia , Transplante de Fígado/métodos , Doadores Vivos , Adulto , Emergências , Hepatectomia , Encefalopatia Hepática/virologia , Hepatite B/complicações , Humanos , Fígado/anatomia & histologia , Testes de Função Hepática , Imageamento por Ressonância Magnética , Masculino , Núcleo Familiar , Coleta de Tecidos e ÓrgãosRESUMO
As more adults undergo transplantation with partial liver grafts, the unique features of these segments and their clinical significance will become apparent. A patient presented with life-threatening hemorrhage from an iatrogenic laceration to a right lobe graft 11 days after transplantation. The creation of a portacaval shunt effectively controlled the bleeding, allowing more elective replacement of the organ with another right lobe graft. The regeneration process combined with increased portal blood flow and relative outflow limitation may have set the stage for this complication. Any disruption of the liver parenchyma during transplantation should be securely repaired and followed cautiously. Portacaval shunting is an option for controlling hemorrhage from the liver in transplant recipients. The timely availability of a second organ was likely the ultimate determinant of survival for this patient.