RESUMEN
BACKGROUND AND OBJECTIVE: LPAC (low phospholipid-associated cholelithiasis) syndrome is a rare genetic form of cholelithiasis. ERCP (endoscopic retrograde cholangiopancreatography) is often used to remove gallstones in the bile duct. No published data is available on the role of ERCP in LPAC syndrome. PATIENTS AND METHODS: In this retrospective cohort study, we included patients diagnosed with LPAC syndrome in a single tertiary referral center between 2009 and 2021. Our aim was to assess the frequency, indications, modalities, results, and complications of ERCP, as well as predictive factors for ERCP, in LPAC syndrome. Independent factors associated with ERCP occurrence were identified using a multivariable Cox regression analysis. RESULTS: ERCP was required in 31.2 % of the 269 patients included for analysis. Among patients who required ERCPs, 78.6 % had the procedure before diagnosis (i.e., starting UDCA). Most common indications were choledocholithiasis (53.6 %) and acute cholangitis (29.5 %). Post ERCP pancreatitis, perforation and bleeding rates were 7.2 %, 2.6 %, and 1.3 %, respectively. Age and history of cholelithiasis in first-degree relatives were associated with a higher risk of ERCP (Hazard-ratio [HR]=1.30 [95 %confidence-interval [CI] 1.04-1.62] and HR=1.88 [95 %CI 1.15-3.07] respectively). Female gender and UDCA intake ≥ 1 year were associated with a lower risk of ERCP (HR=0.49 [95 %CI 0.29-0.82] and HR=0.44 [95 %CI 0.22-0.90] respectively). Median follow-up was 10.8 years. CONCLUSION: One-third of patients with LPAC syndrome undergo sphincterotomy. However, most procedures are performed before diagnosis and UDCA is associated with a lower risk of endoscopic procedure. Earlier diagnosis and treatment with UDCA may further reduce the need for ERCP in patients with LPAC syndrome.
Asunto(s)
Colangiopancreatografia Retrógrada Endoscópica , Colelitiasis , Humanos , Estudios Retrospectivos , Femenino , Masculino , Colangiopancreatografia Retrógrada Endoscópica/efectos adversos , Persona de Mediana Edad , Colelitiasis/complicaciones , Adulto , Estudios de Cohortes , Anciano , Síndrome , Colangitis/etiología , Coledocolitiasis/complicacionesRESUMEN
Primary sclerosing cholangitis (PSC) is strongly associated with several human leukocyte antigen (HLA) haplotypes. Due to extensive linkage disequilibrium and multiple polymorphic candidate genes in the HLA complex, identifying the alleles responsible for these associations has proven difficult. We aimed to evaluate whether studying populations of admixed or non-European descent could help in defining the causative HLA alleles. When assessing haplotypes carrying HLA-DRB1*13:01 (hypothesized to specifically increase the susceptibility to chronic cholangitis), we observed that every haplotype in the Scandinavian PSC population carried HLA-DQB1*06:03. In contrast, only 65% of HLA-DRB1*13:01 haplotypes in an admixed/non-European PSC population carried this allele, suggesting that further assessments of the PSC-associated haplotype HLA-DRB1*13:01-DQA1*01:03-DQB1*06:03 in admixed or multi-ethnic populations could aid in identifying the causative allele.
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Colangitis Esclerosante/genética , Predisposición Genética a la Enfermedad , Cadenas beta de HLA-DQ/genética , Cadenas HLA-DRB1/genética , Haplotipos , Alelos , Colangitis Esclerosante/etnología , Colangitis Esclerosante/inmunología , Etnicidad , Expresión Génica , Frecuencia de los Genes , Cadenas beta de HLA-DQ/clasificación , Cadenas beta de HLA-DQ/inmunología , Cadenas HLA-DRB1/clasificación , Cadenas HLA-DRB1/inmunología , Humanos , Desequilibrio de Ligamiento , Países Escandinavos y Nórdicos , Población BlancaRESUMEN
BACKGROUND: Few epidemiologic data are available regarding biologic liver abnormalities during psoriasis flares. OBJECTIVES: The aim of this study was to assess the prevalence of biological liver test abnormalities (LTA) in a psoriasis population and the risk factors associated with LTA. METHODS: A retrospective cross-sectional study in four hospital dermatology tertiary care centres included patients admitted for severe psoriasis flare between 1st January 2010 and 31st December 2011. During the same period, a control population was selected comprising patients admitted for contact and/or atopic eczema. Data were collected on hospital records and biology software. LTA was defined as serum AST and/or ALT and/or ALP concentration above the upper normal limit (UNL) and/or GGT concentration above 2 UNL. Prevalence of LTA with 95% confidence intervals (95% CI) was compared between the psoriatic and control populations. Factors associated with LTA at P < 0.05 were considered for the final multivariate logistic regression model. RESULTS: Two hundred and forty psoriasis patients and 96 eczema control patients were included. One hundred and fifty-five(64.6%) of the psoriasis patients were male, aged 55 years on average (±17.6); 192 (80.0%) had plaque-type psoriasis (PV) and 52 (21.6%) had localized (n = 32) or generalized (n = 20) pustular psoriasis (PP). Prevalence of LTA was 36% (95% CI, 30-42) in the psoriatic population, significantly higher than in controls (17%, 95% CI 9.5-25). Risk factors independently associated with LTA comprised PV (OR 3.79; 95% CI 1.48-9.65), PP (OR 3.80; 95% CI 1.40-10.25) and previously diagnosed liver disease (underlying hepatic steatosis, viral hepatitis or excessive alcohol consumption) (OR 3.88; 95% CI 2.02-7.45). No association was found with systemic antipsoriatic drug therapies. CONCLUSION: In severe psoriasis, liver impacting comorbidities and/or specific psoriatic inflammation, the latter mostly in PP cases, more than drug-related liver toxicity, appears to predominantly account for LTA. Clinicians should be aware of this, to avoid unjustified withdrawal of useful systemic drugs.
Asunto(s)
Pruebas de Función Hepática , Psoriasis/fisiopatología , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Estudios Retrospectivos , Factores de RiesgoRESUMEN
TNFα has been shown to play a role in hepatitis C virus (HCV)-induced insulin resistance (IR). Polymorphism of the IL28B gene that encodes IFN-lambda 3 may be associated with IR through modulation of TNFα. The aim of this study was to investigate the relationship between IL28B rs12979860 genotype, the level of TNFα activation and the degree of IR in patients with chronic hepatitis C. One hundred and thirty-three nondiabetic genotype 1 HCV-infected patients with biopsy proven noncirrhotic hepatitis C were investigated for IR (using HOMA index), IL28B rs12979860 genotype and fasting circulating levels of soluble receptor 1 of TNFα (sTNFR1) and adipokines: leptin, adiponectin and IL-6. The HOMA-IR was positively correlated with serum levels of leptin (r = 0.35, P < 0.0001) and sTNFR1 (r = 0.35, P < 0.0001) but not with IL-6 or adiponectin. IL28B rs12979860 CC genotype was observed in 35% patients. Genotype CC and nongenotype CC patients were similar in terms of HOMA-IR (means 1.6 ± 0.9 vs 1.7 ± 1.4) and had similar circulating levels of sTNFR1 and adipokines. Independent factors associated with IR were ferritin (OR = 1.002, P = 0.02), leptin (OR = 1.06, P = 0.02) and sTNFR1 (OR = 7.9, P = 0.04). This study suggests that in nondiabetic, noncirrhotic, HCV genotype 1-infected patients, there is no relationship between IL28B rs12979860 genotype and HOMA-IR or sTNFR1 level. HCV-related IR may be mediated through TNFα independent of IL28B genotype.
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Hepatitis C Crónica/complicaciones , Resistencia a la Insulina , Interleucinas/genética , Polimorfismo de Nucleótido Simple , Factor de Necrosis Tumoral alfa/sangre , Adiponectina/sangre , Adulto , Anciano , Biomarcadores/sangre , Femenino , Hepatitis C Crónica/patología , Humanos , Interferones , Interleucina-6/sangre , Leptina/sangre , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Autoimmune hepatitis is a disorder of unknown aetiology that occurs in children and adults of all ages with a female predominance. The spectrum of presentation is wide, ranging from no symptoms to acute liver failure. The diagnosis is based on high level serum gammaglobulins, characteristic circulating autoantibodies and histologic abnormalities (necrosis and inflammation). Autoimmune hepatitis is classified on the basis of the autoantibody pattern: type 1 (antinuclear and/or smooth muscle antibodies) is the classic form whereas type II (liver-kidney microsome 1 antibody) is much less common and occurs mainly in childhood. Mixed forms of autoimmune hepatitis that share features with other putative autoimmune liver diseases, primary biliary cirrhosis and primary sclerosing cholangitis, have been described. Because of therapeutic issues, it is important to distinguish autoimmune hepatitis from other forms of hepatitis and the use of diagnostic scoring systems may be helpful. The treatment of autoimmune hepatitis has not changed for the past 30 years. It consists of corticosteroids associated with azathioprine. This treatment is rapidly effective but usually only suspensive. Relapse after treatment withdrawal is the rule (80% of cases). The main risk factor of recurrence is the degree of residual inflammation on liver biopsy. The frequency of side effects justifies an attempt of drug discontinuation provided that criteria of clinical, biochemical and histological remission are achieved after at least 2 years of treatment.
Asunto(s)
Hepatitis Autoinmune/diagnóstico , Hepatitis Autoinmune/tratamiento farmacológico , HumanosAsunto(s)
Albúminas/uso terapéutico , Colestasis/complicaciones , Soluciones para Diálisis/uso terapéutico , Hemofiltración/métodos , Prurito/terapia , Diálisis Renal/métodos , Ácidos y Sales Biliares/sangre , Colestasis/sangre , Humanos , Dimensión del Dolor , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
BACKGROUND/AIMS: To assess the benefit of the UDCA-budesonide combination in association with mycophenolate mofetil (MMF) in patients with primary biliary cirrhosis (PBC) at high risk of developing cirrhosis or liver failure. METHODS: Inclusion criteria for this three-year open study were: 1) suboptimal biochemical response to one-year UDCA therapy at 13-15 mg/kg/d; 2) significant interface hepatitis without cirrhosis at liver biopsy. Treatment regimen included UDCA (13-15 mg/kg/d), budesonide (6 mg/d) and MMF (1.5 g/d). All patients underwent a control biopsy at three years. RESULTS: Fifteen patients fulfilled the inclusion criteria. Six patients (41%) normalized biochemistries and seven (47%) had a partial but significant biochemical response, as defined by a serum bilirubin less than 17 micromol/L, alanine aminotransferase less than 70 UI/L and alkaline phosphatase less than 250 UI/L. Histological activity and fibrosis were markedly improved. Side effects were minimal or absent. CONCLUSIONS: Triple therapy with UDCA, budesonide and MMF may provide benefit in non-cirrhotic PBC patients with features of severe disease not responding to UDCA.
Asunto(s)
Budesonida/uso terapéutico , Cirrosis Hepática Biliar/tratamiento farmacológico , Ácido Micofenólico/análogos & derivados , Ácido Ursodesoxicólico/uso terapéutico , Adulto , Alanina Transaminasa/sangre , Fosfatasa Alcalina/sangre , Bilirrubina/sangre , Colagogos y Coleréticos/uso terapéutico , Quimioterapia Combinada , Femenino , Glucocorticoides/uso terapéutico , Humanos , Inmunosupresores/uso terapéutico , Cirrosis Hepática/prevención & control , Fallo Hepático/prevención & control , Persona de Mediana Edad , Ácido Micofenólico/uso terapéutico , Índice de Severidad de la EnfermedadRESUMEN
Autoimmune hepatitis (AIH) is a disorder of unknown aetiology that occurs in children and adults of all ages with a female predominance. The spectrum of presentation is wide, ranging from no symptoms to acute liver failure. The diagnosis is based on high level or serum gammaglobulins, characteristic circulating autoantibodies and histologic abnormalities (necrosis and inflammation) in the absence of other causes. AIH is classified on the basis of the autoantibody pattern: type 1 (antinuclear and/or smooth muscle antibodies) is the classic form whereas type 2 (liver-kidney microsome 1 antibody) is much less common and occurs mainly in childhood. Mixed forms of AIH that share features with other putative autoimmune liver diseases, primary biliary cirrhosis and primary sclerosing cholangitis, have been described. Because of therapeutic issues, it is important to distinguish AIH from other forms of hepatitis and the use of diagnostic scoring systems may be helpful. Treatment basis of AIH have not changed for the last 30 years. Initial treatment consists of corticosteroids associated with azathioprine. Budesonide may be at least as effective as systemic corticosteroids and reduces the frequency of side effects in non-cirrhotic patients. Long-term treatment consists of azathioprine. This treatment is rapidly effective but usually only suspensive since relapse after treatment withdrawal is the rule (80 % of cases). The probability of relapse is lower in case of complete biochemical response defined by normalization of transaminases, gamma-globulins and IgG and in case of histological response defined by the lack of interface hepatitis. The frequency of side effects justifies an attempt of drug discontinuation provided that criteria of clinical, biochemical and histological remission are achieved after at least 2 years of treatment.
Asunto(s)
Hepatitis Autoinmune/diagnóstico , Hepatitis Autoinmune/tratamiento farmacológico , Anticuerpos Antinucleares/sangre , Autoanticuerpos/sangre , Biomarcadores/sangre , Diagnóstico Diferencial , Quimioterapia Combinada , Femenino , Glucocorticoides/administración & dosificación , Glucocorticoides/efectos adversos , Hepatitis Autoinmune/inmunología , Humanos , Inmunoglobulina G/sangre , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Persona de Mediana Edad , Resultado del TratamientoAsunto(s)
Colestasis/diagnóstico , Colestasis/terapia , Adulto , Femenino , Humanos , Persona de Mediana EdadRESUMEN
Liver dysfunction during pregnancy can be related or not to pregnancy itself. The purpose of this review is to summarize the possible causes of liver dysfunction during pregnancy and their management. Liver dysfunction during pregnancy can be chronic or acute, independent or specific to pregnancy. Management of liver disease can be different during pregnancy. The knowledge of liver dysfunction during pregnancy is of help for a better management of the mother in order to avoid maternal and fetal mortality and morbidity.
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Hepatopatías/diagnóstico , Hepatopatías/terapia , Complicaciones del Embarazo/diagnóstico , Complicaciones del Embarazo/terapia , Femenino , Humanos , Pruebas de Función Hepática , EmbarazoRESUMEN
Fulminant hepatitis of unknown origin remain a significant cause of mortality, for which liver transplantation is often considered as the only therapeutic option. In retrospective studies, human herpesvirus 6 (HHV-6) infections have been associated with such diseases, but the diagnosis of HHV-6 infection of the liver is rarely established during the acute phase of liver failure. Using real-time polymerase chain reaction (PCR), we diagnosed two cases of severe acute liver failure (ALF) related to HHV-6 occurring in immunocompetent young adults. Both cases had a favourable outcome, one after valganciclovir therapy, one after liver transplantation associated with ganciclovir. Viral origin was evidenced in each case by the detection of high amounts of HHV-6 DNA in liver tissue by the PCR assay. The decrease of intrahepatic viral load after therapeutic intervention was also monitored by quantitative PCR and paralleled in the two cases the clinical improvement. Diagnosis of HHV-6 infection must be systematically evoked in case of unexplained ALF, since it might lead to specific therapeutic interventions, in addition of liver transplantation.
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Antivirales/uso terapéutico , Ganciclovir/uso terapéutico , Herpesvirus Humano 6 , Fallo Hepático Agudo/virología , Trasplante de Hígado/métodos , Infecciones por Roseolovirus/terapia , Administración Oral , Adulto , Femenino , Ganciclovir/análogos & derivados , Humanos , Inmunocompetencia , Fallo Hepático Agudo/tratamiento farmacológico , Fallo Hepático Agudo/cirugía , Infecciones por Roseolovirus/tratamiento farmacológico , Infecciones por Roseolovirus/cirugía , Resultado del Tratamiento , ValganciclovirRESUMEN
Low pretreatment viral load has consistently been shown to be an independent predictor of sustained response (SR) in patients with chronic hepatitis C infection. We assessed the efficacy of interferon (IFN) plus ribavirin vs IFN alone in low viraemic patients (<2 millions copies/mL) who had relapsed to a previous course of IFN and the efficacy of 24 vs 48 week combination therapy in high viraemic patients. Two hundred and ninety-seven patients were randomly assigned to one of the four regimens after stratification on pretreatment viral load. All patients received IFN-alpha2b (6 million units thrice weekly for 24 weeks and 3 million units thrice weekly for 24 weeks). Patients with low viraemia received either IFN-alpha2b alone for 48 weeks (R1: 42 patients) or IFN-alpha2b plus ribavirin (600 mg/day) for 24 weeks and IFN-alpha2b alone for the next 24 weeks (R2: 48 patients). Patients with high viral load received either IFN-alpha2b plus ribavirin for 24 weeks and then IFN-alpha2b alone for the next 24 weeks (R3: 104 patients) or IFN-alpha2b plus ribavirin for 48 weeks (R4: 103 patients). In low viraemic patients the rate of SR was 37.7% in group R1 and 59.6% in group R2 (P < 0.05). In high viraemic patients, the rate of SR was 44.7% in group R3 and 51.4% in group R4 (P: NS). Thirty-one patients discontinued treatment (10.4%) without difference regarding treatment regimen. In the regimen using ribavirin we found no difference in terms of SR between patients receiving a dose of ribavirin below 10.6 mg/kg/day (55%) or over 10.6 mg/kg/day (58%). Histological improvement occurred in 70.2% of patients regardless of the regimen. Logistic regression showed that genotype 2 and 3, Knodell score <6 and alanine aminotransferase pretreatment level >3 x upper limit of normal were significantly and independently correlated with SR. In low viraemic patients who relapsed to a previous IFN treatment, combination therapy using high-dose IFN and low-dose ribavirin is better than high-dose IFN alone. In high viraemic patients there was no benefit in increasing the duration of combination therapy from 24 to 48 weeks. In this study, it was found that low dose of ribavirin can be used safely and there is no effect of ribavirin dose on SR.
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Antivirales/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Ribavirina/uso terapéutico , Viremia/tratamiento farmacológico , Adulto , Quimioterapia Combinada , Femenino , Hepacivirus/efectos de los fármacos , Hepacivirus/fisiología , Hepatitis C Crónica/virología , Humanos , Interferón alfa-2 , Masculino , Persona de Mediana Edad , Estudios Prospectivos , ARN Viral/sangre , Proteínas Recombinantes , Recurrencia , Retratamiento , Resultado del Tratamiento , Carga Viral , Viremia/virologíaRESUMEN
A-Type lamins, arising from the LMNA gene, are intermediate filaments proteins that belong to the lamina, a ubiquitous nuclear network. Naturally occurring mutations in these proteins have been shown to be responsible for several distinct diseases that display skeletal and/or cardiac muscle or peripheral nerve involvement. These include familial partial lipodystrophy of the Dunnigan type and the mandibuloacral dysplasia syndrome. The pathophysiology of this group of diseases, often referred to as laminopathies, remains elusive. We report a new condition in a 30-yr-old man exhibiting a previously undescribed heterozygous R133L LMNA mutation. His phenotype associated generalized acquired lipoatrophy with insulin-resistant diabetes, hypertriglyceridemia, hepatic steatosis, hypertrophic cardiomyopathy with valvular involvement, and disseminated whitish papules. Immunofluorescence microscopic analysis of the patient's cultured skin fibroblasts revealed nuclear disorganization and abnormal distribution of A-type lamins, similar to that observed in patients harboring other LMNA mutations. This observation broadens the clinical spectrum of laminopathies, pointing out the clinical variability of lipodystrophy and the unreported possibility of hypertrophic cardiomyopathy and skin involvement. It emphasizes the fact that the diagnosis of genetic alterations in A-type lamins requires careful and complete clinical and morphological investigations in patients regardless of the presenting signs.
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Cardiomiopatía Hipertrófica/genética , Diabetes Mellitus/genética , Hígado Graso/genética , Resistencia a la Insulina , Lamina Tipo A/genética , Lipodistrofia/genética , Mutación , Adulto , Secuencia de Aminoácidos , Animales , Secuencia Conservada , Humanos , Lamina Tipo A/química , Masculino , Datos de Secuencia Molecular , Enfermedades de la Piel/genéticaRESUMEN
OBJECTIVES: The outcome of dysthyroidism and the presence of antithyroid antibodies in patients with chronic hepatitis C virus (HCV) infection receiving interferon-alpha therapy is clearly established. However, the prevalence and the specificity of antithyroid antibodies in HCV patients before interferon-alpha therapy remain controversial. The aim of the present study is to clarify within a large population of HCV patients the prevalence of antithyroid antibodies before interferon-alpha therapy and to determine whether their immunodominant antigen is the same as described in autoimmune thyroiditis. METHODS: Sera from 99 patients with chronic hepatitis C before (n = 99) and after (n = 37) interferon-alpha treatment were investigated for the presence of antimicrosomal and antithyroperoxidase antibodies assessed by indirect immunofluorescence and ELISA, respectively. Dot blotting on human thyroid lysate was designed to further characterize these autoantibodies. Data were compared to those obtained with sera of patients with autoimmune thyroiditis (n = 75) and healthy subjects (n = 96). RESULTS: In HCV patients, antimicrosomal antibodies were found with a higher proportion before interferon-alpha therapy (12.1%) than after therapy (8%). Thyroperoxidase constitutes the main antigen in only 4% before treatment, a prevalence similar to that observed in healthy controls. CONCLUSIONS: The prevalence of antithyroid antibodies is low in patients with chronic hepatitis C before interferon-alpha therapy. Thyroperoxidase may not be their main target. Further studies are required to determine whether HCV infection leads to a breakdown of tolerance to a thyroid self-protein other than thyroperoxidase.
Asunto(s)
Autoanticuerpos/inmunología , Autoantígenos/inmunología , Hepatitis C Crónica/inmunología , Yoduro Peroxidasa , Proteínas de Unión a Hierro , Tiroiditis Autoinmune/inmunología , Adulto , Anciano , Antivirales/uso terapéutico , Ensayo de Inmunoadsorción Enzimática , Femenino , Técnica del Anticuerpo Fluorescente Indirecta , Hepatitis C Crónica/tratamiento farmacológico , Humanos , Interferón-alfa/uso terapéutico , Masculino , Persona de Mediana Edad , Glándula Tiroides/inmunologíaRESUMEN
BACKGROUND/AIMS: To determine whether the apolipoprotein E (apo-E) polymorphism is associated with the risk of primary biliary cirrhosis (PBC), the severity of the disease and its response to ursodeoxycholic acid (UDCA) therapy. METHODS: The apo-E genotype was determined in 72 PBC patients. Genotype and allele distributions were compared with those found in the French general population. Laboratory parameters obtained before and after 1- and 4-year UDCA treatment were compared according to the apo-E allele carrier status. RESULTS: Apo-E allele and genotype distributions were similar between PBC patients and the general population. At the time of diagnosis, the epsilon4 allele carriers were younger (P < 0.05), had higher bilirubin (P < 0.05) and IgG (P < 0.001) levels and a lower prothrombin index (P < 0.01) than epsilon2 (homozygous + heterozygous) or epsilon3 homozygous allele carriers. After 4-year UDCA therapy, the decrease in serum alkaline phosphatase and in alanine and aspartate aminotransferase activities was lower in percentage in the epsilon4 than in other epsilon allele carriers (P < 0.01). CONCLUSIONS: Although apo-E polymorphism does not appear to confer susceptibility to PBC, it probably influences PBC progression and response to UDCA. The epsilon4 allele may identify patients with high risk of severe disease and poor response to treatment.
Asunto(s)
Apolipoproteínas E/genética , Cirrosis Hepática Biliar/genética , Polimorfismo Genético , Alanina Transaminasa/sangre , Aspartato Aminotransferasas/sangre , Biomarcadores , Estudios Transversales , Humanos , Cirrosis Hepática Biliar/sangre , Cirrosis Hepática Biliar/tratamiento farmacológico , Estudios Retrospectivos , Ácido Ursodesoxicólico/uso terapéuticoRESUMEN
Sustained viral suppression using monotherapy with interferon alfa (IFN-alpha) or lamivudine can only be achieved in a small percentage of patients with chronic hepatitis B. The concomitant administration of lamivudine and IFN-alpha does not enhance efficacy. We postulated that the optimal timing of therapy might be sequential treatment with lamivudine and IFN-alpha. The aim of this study was therefore to assess the efficacy of sequential treatment in patients resistant to IFN-alpha alone. Fourteen male patients, with a median age of 40 years, nonresponders to IFN-alpha with hepatitis B virus (HBV) DNA > 100 pg/mL (branched DNA [bDNA] Chiron) and positive hepatitis B e antigen (HBeAg) in 11 of 14 patients, were treated with lamivudine 100 mg/d alone for 20 weeks, then with both IFN-alpha2b 5 MU 3 times per week and lamivudine for 4 weeks, and lastly with IFN-alpha alone for 24 weeks. At the end of lamivudine therapy, all patients had undetectable serum HBV DNA, and none exhibited an emergence of HBV polymerase mutant or breakthrough. Sustained serum HBV-DNA clearance 6 months after the end of sequential treatment was achieved in 8 of 14 patients, HBeAg-to-anti-HBe seroconversion in 5 of 11 patients, and HBeAg and hepatitis B surface antigen (HBsAg) seroconversions in 3 of 14 patients (anti-HBs > 100 IU/mL). All sustained responders had normalized their alanine transaminase (ALT) values and exhibited histologic improvements. In conclusion, the results of this pilot study suggest that sequential treatment with lamivudine and IFN-alpha can induce a sustained virologic response, including HBs seroconversion, in patients with chronic hepatitis B not responding to IFN-alpha alone, without the selection of drug-resistant mutants. This therapeutic schedule warrants further evaluation in clinical trials.