RESUMEN
The adaptive immune system is a diverse ecosystem that responds to pathogens by selecting cells with specific receptors. While clonal expansion in response to particular immune challenges has been extensively studied, we do not know the neutral dynamics that drive the immune system in the absence of strong stimuli. Here, we learn the parameters that underlie the clonal dynamics of the T cell repertoire in healthy individuals of different ages, by applying Bayesian inference to longitudinal immune repertoire sequencing (RepSeq) data. Quantifying the experimental noise accurately for a given RepSeq technique allows us to disentangle real changes in clonal frequencies from noise. We find that the data are consistent with clone sizes following a geometric Brownian motion and show that its predicted steady state is in quantitative agreement with the observed power-law behavior of the clone-size distribution. The inferred turnover time scale of the repertoire increases with patient age and depends on the clone size in some individuals.
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Ecosistema , Linfocitos T , Humanos , Teorema de Bayes , Células Clonales , Receptores de Antígenos de Linfocitos T/genéticaRESUMEN
OBJECTIVE: The aim of the study was to compare SURG vs SOR regarding the OS and progression-free survival (PFS) in a real-world clinical scenario. BACKGROUND DATA: The treatment for advanced nonmetastatic HCC belonging to the Barcelona Clinic Liver Cancer stage C (BCLC C) is still controversial. METHODS: BCLC C patients without extrahepatic spread and tumoral invasion of the main portal trunk were considered. Surgical patients were obtained from the HE.RC.O.LE.S. Register, whereas sorafenib patients were obtained from the ITA.LI.CA register The inverse probability weighting (IPW) method was adopted to balance the confounders between the 2 groups. RESULTS: Between 2008 and 2019, 478 patients were enrolled: 303 in SURG and 175 in SOR group. Eastern Cooperative Oncological Group Performance Status (ECOG-PS), presence of cirrhosis, steatosis, Child-Pugh grade, hepatitis B virus and hepatitis C virus, alcohol intake, collateral veins, bilobar disease, localization of the tumor thrombus, number of nodules, alpha-fetoprotein, age, and Charlson Comorbidity index were weighted by IPW to create two balanced pseudo-populations: SURG = 374 and SOR = 263. After IPW, 1-3-5âyears OS was 83.6%, 68.1%, 55.9% for SURG, and 42.3%, 17.8%, 12.8% for SOR (P < 0.001). Similar trends were observed after subgrouping patients by ECOG-PS = 0 and ECOG-PS >0, and by the intrahepatic location of portal vein invasion. At Cox regression, sorafenib treatment (hazard ratio 4.436; 95% confidence interval 3.19-6.15; P < 0.001) and Charlson Index (hazard ratio 1.162; 95% confidence interval 1.06-1.27; P = 0.010) were the only independent predictors of mortality. PFS at 1-3-5âyears were 65.9%, 40.3%, 24.3% for SURG and 21.6%, 3.5%, 2.9% for SOR (P = 0.007). CONCLUSIONS: In BCLC C patients without extrahepatic spread but with intrahepatic portal invasion, liver resection, if feasible, was followed by better OS and PFS compared with sorafenib.
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Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/cirugía , Hepatectomía , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/cirugía , Estadificación de Neoplasias , Niacinamida/uso terapéutico , Compuestos de Fenilurea/uso terapéutico , Estudios Retrospectivos , Sorafenib/uso terapéutico , Resultado del TratamientoRESUMEN
In recent decades, following the spread of obesity, metabolic dysfunction has come to represent the leading cause of liver disease. The classical clinical presentation of the cirrhotic patient has, therefore, greatly changed, with a dramatic increase in subjects who appear overweight or obese. Due to an obesogenic lifestyle (lack of physical activity and overall malnutrition, with an excess of caloric intake together with a deficit of proteins and micronutrients), these patients frequently develop a complex clinical condition defined as sarcopenic obesity (SO). The interplay between cirrhosis and SO lies in the sharing of multiple pathogenetic mechanisms, including malnutrition/malabsorption, chronic inflammation, hyperammonemia and insulin resistance. The presence of SO worsens the outcome of cirrhotic patients, affecting overall morbidity and mortality. International nutrition and liver diseases societies strongly agree on recommending the use of food as an integral part of the healing process in the comprehensive management of these patients, including a reduction in caloric intake, protein and micronutrient supplementation and sodium restriction. Based on the pathophysiological paths shared by cirrhosis and SO, this narrative review aims to highlight the nutritional interventions currently advocated by international guidelines, as well as to provide hints on the possible role of micronutrients and nutraceuticals in the treatment of this multifaceted clinical condition.
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Hepatopatías , Desnutrición , Sarcopenia , Humanos , Sarcopenia/tratamiento farmacológico , Obesidad/terapia , Obesidad/tratamiento farmacológico , Cirrosis Hepática/terapia , Cirrosis Hepática/tratamiento farmacológico , Hepatopatías/tratamiento farmacológico , Desnutrición/tratamiento farmacológico , Micronutrientes/uso terapéuticoRESUMEN
BACKGROUND: MASLD is a prevalent chronic liver condition with substantial clinical implications. This study aimed to assess the effectiveness of three new, elastography-based, scoring systems for advanced fibrosis ≥F3 (Agile 3+), cirrhosis F4 (Agile 4), and fibrotic NASH: NASH + NAS ≥4 + F≥2 (FAST score), in a cohort of biopsy-proven NAFLD meeting MASLD criteria. Our secondary aim was to compare their diagnostic performances with those of other fibrosis prediction tools: LSM-VCTE alone, and common, easily available scores (FIB-4 or APRI). METHODS: Single-center, retrospective study, on consecutive patients with baseline laboratory tests, liver biopsy, and reliable LSM-VCTE measurements. The discrimination between tests was evaluated by analyzing the AUROCs. Dual cut-off approaches were applied to rule-out and rule-in ≥F3, F4 and fibrotic NASH. We tested previously reported cut-off values and provided our best thresholds to achieve Se ≥85%, Se ≥90%, and Sp ≥90%, Sp ≥95%. RESULTS: Among 246 patients, 113 (45.9%) were women, and 75 (30.5%) presented diabetes. Agile 3+ and Agile 4 demonstrated excellent performance in identifying ≥F3 and F4, achieving AUROCs of 0.909 and 0.968, while the FAST score yielded acceptable results in distinguishing fibrotic NASH. When compared to FIB-4 and LSM-VCTE, both Agile 3+ and Agile 4 performed better than FIB-4 and had a similar performance to LSM-VCTE, but with higher diagnostic accuracy, hence reducing the grey zone. CONCLUSION: Agile 3+ and Agile 4 are reliable, non-invasive tests for identifying advanced fibrosis or cirrhosis in MASLD patients, while FAST score demonstrates moderate performance in identifying fibrotic NASH.
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Diagnóstico por Imagen de Elasticidad , Cirrosis Hepática , Enfermedad del Hígado Graso no Alcohólico , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Biopsia/métodos , Diagnóstico por Imagen de Elasticidad/métodos , Hígado/patología , Cirrosis Hepática/patología , Cirrosis Hepática/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Estudios Retrospectivos , Índice de Severidad de la EnfermedadRESUMEN
Non-alcoholic fatty liver disease (NAFLD) is a potentially progressive condition characterized by the presence of fat in more than 5% of hepatocytes, representing the hepatic expression of metabolic syndrome (MetS). A reduction of at least 5-7% in initial body weight improves the metabolic profile underlying NAFLD. The aim of our study was to evaluate the effects of the COVID-19 lockdown on a cohort of non-advanced NAFLD Italian outpatients. We identified 43 patients with 3 available time point visits in our center: first visit (T0) when behavioral indications aimed at controlling MetS were provided, a pre-COVID visit (T1) and a post-COVID visit (T2). During the lockdown, an online compilation of validated psychological tests (SRQ-20, EQ5D, SF-12 and STAI) and a specifically formulated questionnaire for NAFLD was presented to our cohort and completed by 14 consenting patients. Patients who had lost more than 5% of the initial weight at T1 (9 subjects, 21%) maintained the results even at T2, with an overall reduction in BMI and liver stiffness; patients who had not lost the desired weight at T1 (34 subjects, 79%) displayed a further increase in BMI and visceral adiposity at T2. Of interest is that patients in the latter group reported signs of psychological suffering. Our data demonstrated that the setting of good counseling was effective in controlling the metabolic disorder underlying NAFLD in our cohort of outpatients. Given the need for patients to play an active role in the behavioral therapy for NAFLD, we advocate that a multidisciplinary approach be adopted, including a psychological support to obtain the best results over time.
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COVID-19 , Síndrome Metabólico , Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Factores de Riesgo , Pacientes Ambulatorios , Pandemias , COVID-19/epidemiología , Control de Enfermedades Transmisibles , Síndrome Metabólico/metabolismoRESUMEN
The role of moderate alcohol consumption in the evolution of NAFLD is still debated. The aim of this study is to evaluate the impact of current and lifelong alcohol consumption in patients with NAFLD. From 2015 to 2020, we enrolled 276 consecutive patients fulfilling criteria of NAFLD (alcohol consumption up to 140 g/week for women and 210 g/week for men). According to their current alcohol intake per week, patients were divided in: abstainers, very low consumers (C1: <70 g/week) and moderate consumers (C2). We created a new tool, called LACU (Lifetime Alcohol Consuming Unit) to estimate the alcohol exposure across lifetime: 1 LACU was defined as 7 alcohol units per week for 1 drinking year. Patients were divided into lifelong abstainers and consumers and the latter furtherly divided into quartiles: Q1-Q4. Stratification according to alcohol intake, both current and cumulative as estimated by LACU, showed that very low consumers (C1 and Q1-Q3) displayed lower frequency of cirrhosis and hepatocellular carcinoma compared to abstainers and moderate consumers (C2 and Q4). We can speculate that up to one glass of wine daily in the context of a Mediterranean diet may be a long-term useful approach in selected NAFLD patients.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Enfermedad del Hígado Graso no Alcohólico , Consumo de Bebidas Alcohólicas/efectos adversos , Consumo de Bebidas Alcohólicas/epidemiología , Carcinoma Hepatocelular/complicaciones , Carcinoma Hepatocelular/etiología , Femenino , Fibrosis , Humanos , Cirrosis Hepática/complicaciones , Neoplasias Hepáticas/epidemiología , Neoplasias Hepáticas/etiología , Masculino , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/etiología , Prevalencia , Factores de RiesgoRESUMEN
UNLABELLED: Immunotolerance is maintained by regulatory T cells (Tregs), including CD4(+)CD25(hi), CD8(+)CD28(-), gammadelta, and CD3(+)CD56(+) [natural killer T (NKT)] cells. CD4(+)CD25(hi) cells are impaired in children with autoimmune hepatitis (AIH). Little is known about Tregs in adults with AIH. The aim of this study was to investigate the frequency and function of Treg subsets in adult patients with AIH during periods of active disease and remission. Forty-seven AIH patients (16 with active disease and 31 in remission) and 28 healthy controls were studied. Flow cytometry was used to evaluate surface markers and function-related intracellular molecules in gammadelta, CD8(+)CD28(-), NKT, and CD4(+)CD25(hi) cells. CD4(+)CD25(hi) T cell function was determined by the ability to suppress proliferation and interferon gamma (IFN-gamma) production by CD4(+)CD25(-) target cells. Liver forkhead box P3-positive (FOXP3(+)) cells were sought by immunohistochemistry. In AIH patients, particularly during active disease, CD4(+)CD25(hi) T cells were fewer, expressed lower levels of FOXP3, and were less effective at inhibiting target cell proliferation versus healthy controls. Moreover, although the numbers of CD8(+)CD28(-) T cells were similar in AIH patients and healthy controls, NKT cells were numerically reduced, especially during active disease, and produced lower quantities of the immunoregulatory cytokine interleukin-4 versus controls. In contrast, gammadelta T cells in AIH patients were more numerous versus healthy controls and had an inverted Vdelta1/Vdelta2 ratio and higher IFN-gamma and granzyme B production; the latter was correlated to biochemical indices of liver damage. There were few FOXP3(+) cells within the portal tract inflammatory infiltrate. CONCLUSION: Our data show that the defect in immunoregulation in adult AIH is complex, and gammadelta T cells are likely to be effectors of liver damage.
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Hepatitis Autoinmune/clasificación , Hepatitis Autoinmune/fisiopatología , Subgrupos de Linfocitos T/patología , Subgrupos de Linfocitos T/fisiología , Linfocitos T Reguladores/patología , Linfocitos T Reguladores/fisiología , Adolescente , Adulto , Anciano , Antígenos CD28/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Linfocitos T CD8-positivos/fisiología , Estudios de Casos y Controles , Proliferación Celular , Femenino , Factores de Transcripción Forkhead/metabolismo , Granzimas/metabolismo , Hepatitis Autoinmune/patología , Humanos , Interferón gamma/metabolismo , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/patología , Células Asesinas Naturales/fisiología , Masculino , Persona de Mediana Edad , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Adulto JovenRESUMEN
More than 90% of cases of hepatocellular carcinoma (HCC) occurs in patients with cirrhosis, of which hepatitis B virus and hepatitis C virus are the leading causes, while the tumor less frequently arises in autoimmune liver diseases. Advances in understanding tumor immunity have led to a major shift in the treatment of HCC, with the emergence of immunotherapy where therapeutic agents are used to target immune cells rather than cancer cells. Regulatory T cells (Tregs) are the most abundant suppressive cells in the tumor microenvironment and their presence has been correlated with tumor progression, invasiveness, as well as metastasis. Tregs are characterized by the expression of the transcription factor Foxp3 and various mechanisms ranging from cell-to-cell contact to secretion of inhibitory molecules have been implicated in their function. Notably, Tregs amply express checkpoint molecules such as cytotoxic T lymphocyte-associated antigen 4 and programmed cell-death 1 receptor and therefore represent a direct target of immune checkpoint inhibitor (ICI) immunotherapy. Taking into consideration the critical role of Tregs in maintenance of immune homeostasis as well as avoidance of autoimmunity, it is plausible that targeting of Tregs by ICI immunotherapy results in the development of immune-related adverse events (irAEs). Since the use of ICI becomes common in oncology, with an increasing number of new ICI currently under clinical trials for cancer treatment, the occurrence of irAEs is expected to dramatically rise. Herein, we review the current literature focusing on the role of Tregs in HCC evolution taking into account their opposite etiological function in viral and autoimmune chronic liver disease, and we discuss their involvement in irAEs due to the new immunotherapies.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Factores de Transcripción Forkhead , Humanos , Inmunoterapia , Linfocitos T Reguladores , Factores de Transcripción , Microambiente TumoralRESUMEN
OBJECTIVES: Some patients with primary biliary cirrhosis (PBC) have antinuclear antibodies (ANAs). These ANAs include the "multiple nuclear dots" (MND) staining pattern, targeting promyelocytic leukemia protein (PML) nuclear body (NB) components, such as "speckled 100-kD" protein (Sp100) and PML. A new PML NB protein, designated as Sp140, was identified using serum from a PBC patient. The aim of this study was to analyze the immune response against Sp140 protein in PBC patients. METHODS: We studied 135 PBC patients and 157 pathological controls with type 1 autoimmune hepatitis, primary sclerosing cholangitis, and systemic lupus erythematosus. We used indirect immunofluorescence and a neuroblastoma cell line expressing Sp140 for detecting anti-Sp140 antibodies, and a commercially available immunoblot for detecting anti-Sp100 and anti-PML antibodies. RESULTS: Anti-Sp140 antibodies were present in 20 (15%) PBC patients but not in control samples, with a higher frequency in antimitochondrial antibody (AMA)-negative cases (53 vs. 9%, P<0.0001). Anti-Sp140 antibodies were found together with anti-Sp100 antibodies in all but one case (19 of 20, 90%) and with anti-PML antibodies in 12 (60%) cases. Anti-Sp140 positivity was not associated with a specific clinical feature of PBC. CONCLUSIONS: Our study identifies Sp140 as a new, highly specific autoantigen in PBC for the first time. The very frequent coexistence of anti-Sp140, anti-Sp100 and anti-PML antibodies suggests that the NB is a multiantigenic complex in PBC and enhances the diagnostic significance of these reactivities, which are particularly useful in AMA-negative cases.
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Antígenos Nucleares/inmunología , Autoantígenos/inmunología , Cirrosis Hepática Biliar/inmunología , Factores de Transcripción/inmunología , Adolescente , Adulto , Anciano , Anticuerpos Antinucleares/sangre , Anticuerpos Antinucleares/inmunología , Antígenos Nucleares/sangre , Autoantígenos/sangre , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Colangitis Esclerosante/inmunología , Femenino , Técnica del Anticuerpo Fluorescente Indirecta , Hepatitis Autoinmune/inmunología , Humanos , Immunoblotting , Italia , Cirrosis Hepática Biliar/sangre , Lupus Eritematoso Sistémico/inmunología , Masculino , Persona de Mediana Edad , Estadísticas no Paramétricas , Factores de Transcripción/sangreRESUMEN
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a global epidemic involving 20-40% of the general population. NAFLD is rapidly becoming the leading cause of hepatocellular carcinoma (HCC) worldwide. Knowledge about NAFLD-HCC peculiar features is needed to understand this emerging disease better. OBJECTIVE: To review the current literature about the epidemiological, pathogenic and clinical features characterising the NAFLD and distinguishing it from HCC of other etiologies. METHODS: A systematic review of the literature (PubMed and Medline) using the following string ("Non-alcoholic Fatty Liver Disease"[Mesh] and "Carcinoma, Hepatocellular"[Mesh]). Particular relevance was given to papers published in the last five years as well as previously published manuscript very relevant to this topic according to the experience of the authors. RESULTS: A total of 244 original papers in humans in English literature were analysed. Inherent difficulties in the identification of high-risk subjects and the possibility of occurrence in non-cirrhotic livers are peculiar characteristics of NAFLD-HCC hampering surveillance programs. The consequently delayed diagnosis limits access to surgical procedures and impacts on survival. After correction for tumour burden, however, the survival is not different from that of viral HCC, suggesting that NAFLD-HCC is not intrinsically a more aggressive malignancy. CONCLUSION: A great deal of effort is needed to improve the clinical outcome of NAFLD-HCC, especially in terms of prevention, surveillance protocols, and identification of drug modifying the natural history of the underlying liver disease. The outcome of these efforts will significantly impact global HCC-related costs and mortality.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Enfermedad del Hígado Graso no Alcohólico , Carcinoma Hepatocelular/patología , Humanos , Hígado/patología , Cirrosis Hepática/patología , Neoplasias Hepáticas/patología , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/epidemiologíaRESUMEN
BACKGROUND/AIMS: Autoimmune hepatitis affects mainly women. It is subdivided into type 1 and type 2 according to the autoantibody profile and without immunosuppression usually evolves to cirrhosis and end-stage liver failure. METHODS: We evaluated clinical, biochemical, immunological and genetic features and treatment response of 163 consecutive Italian patients with autoimmune hepatitis. RESULTS: At diagnosis, type 1 autoimmune hepatitis showed more inflamed liver histology and more pronounced cholestasis, whereas type 2 was more common in children. Male and female patients shared similar clinical, biochemical and immunological features. Of 89 patients with 5-year follow-up or longer, 23 patients irrespective of presenting clinical, biochemical and immunological features achieved complete remission (normal transaminases and gammaglobulin levels) which was maintained with minimal steroid dosage; attempt at treatment withdrawal led to disease exacerbation. Complete responders had more often HLA DRB1*0401 (p = 0.011) and their risk of disease progression was lower (p < 0.0001). CONCLUSIONS: Type 1 and type 2 autoimmune hepatitis is one and the same disease. Autoimmune hepatitis has similar features in male and female patients. HLA DRB1*0401 positive patients are more likely to achieve complete remission. Continuous low-dose steroids are necessary to maintain remission, significantly reducing the risk of disease progression.
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Hepatitis Autoinmune , Adolescente , Adulto , Factores de Edad , Preescolar , Femenino , Antígenos HLA-DR/genética , Cadenas HLA-DRB1 , Hepatitis Autoinmune/clasificación , Hepatitis Autoinmune/tratamiento farmacológico , Hepatitis Autoinmune/inmunología , Hepatitis Autoinmune/patología , Humanos , Inmunosupresores/uso terapéutico , Italia , Masculino , Persona de Mediana Edad , Pronóstico , Caracteres Sexuales , Esteroides/uso terapéutico , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND/AIMS: Anti-liver/kidney microsomal antibody type 1 (anti-LKM1), a serological marker of type 2 autoimmune hepatitis, is also detected in a small proportion of patients with hepatitis C. This study aimed to evaluate clinical features and effect of antiviral therapy in patients with hepatitis C who are anti-LKM1 positive. METHODS: Sixty consecutive anti-LKM1 positive and 120 age and sex-matched anti-LKM1 negative chronic hepatitis C patients were assessed at diagnosis and during follow-up. Of these, 26 anti-LKM1 positive and 72 anti-LKM1 negative received antiviral therapy. Anti-LKM1 was detected by indirect immunofluorescence and immunoblot. Number of HCV-infected hepatocytes and intrahepatic CD8+ lymphocytes was determined by immunohistochemistry. RESULTS: At diagnosis anti-LKM1 positive patients had higher IgG levels and more intrahepatic CD8+ lymphocytes (p 0.022 and 0.046, respectively). Viral genotypes distribution and response to therapy were identical. Hepatic flares during antiviral treatment only occurred in a minority of patients in concomitance with anti-LKM1 positivity. CONCLUSIONS: Immune system activation is more pronounced in anti-LKM1 positive patients with hepatitis C, possibly representing the expression of autoimmune mechanisms of liver damage. Antiviral treatment is as beneficial in these patients as in anti-LKM1 negative patients, and the rare necroinflammatory flares are effectively controlled by corticosteroids, allowing subsequent resumption of antiviral therapy.
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Antivirales/uso terapéutico , Autoanticuerpos/sangre , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/inmunología , Adolescente , Adulto , Alanina Transaminasa/sangre , Autoinmunidad , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Estudios de Cohortes , Femenino , Hepatitis C Crónica/patología , Hepatitis C Crónica/virología , Humanos , Inmunoglobulina G/sangre , Interferones/uso terapéutico , Riñón/inmunología , Hígado/inmunología , Hígado/patología , Hígado/fisiopatología , Hígado/virología , Masculino , Microsomas/inmunología , Persona de Mediana Edad , Ribavirina/uso terapéutico , Adulto JovenRESUMEN
OBJECTIVES: During the last decade patients with concomitant clinical, biochemical, immunoserological, and histological features of both autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) were sporadically described, but definite diagnostic criteria and specific serological markers to support the diagnosis of AIH/PBC overlap syndrome (AIH/PBC OS) are still lacking. METHODS: Clinical, biochemical, and histological features, autoantibody profile, and treatment response of 15 patients with coexistent hepatitic and cholestatic liver damage, all fulfilling strict diagnostic criteria for both AIH and PBC, were compared with those of 120 patients with pure PBC and 120 patients with pure AIH. RESULTS: At diagnosis, the AIH/PBC OS patients' median age was 51 years, similar to that of the PBC patients (52 years, P=NS), but significantly higher than that of the AIH patients (40 years, P=0.04). Anti-dsDNA antibodies were detected in 60% of AIH/PBC OS patients, but only in 4% of PBC patients and 26% of AIH patients (P<0.0001 and 0.01, respectively). Double positivity for antimitochondrial antibodies (AMA) and anti-dsDNA was present in 47% of those with AIH/PBC OS, but only in 2% of the pathological controls (P<0.0001; specificity: 98; 95% confidence interval (CI): 97-99.2; positive likelihood ratio: 28; 95% CI: 9.8-79.4). Combined therapy (ursodeoxycholic acid (UDCA) plus steroids) achieved biochemical response in 77% of AIH/PBC OS patients. CONCLUSIONS: Concomitant AMA/anti-dsDNA seropositivity can be considered the serological profile of AIH/PBC OS. The combination of UDCA and steroids is effective in achieving persistent biochemical amelioration in most AIH/PBC OS patients.
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Anticuerpos Antinucleares/inmunología , Hepatitis Autoinmune/inmunología , Cirrosis Hepática Biliar/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Niño , Preescolar , Femenino , Técnica del Anticuerpo Fluorescente Indirecta , Hepatitis Autoinmune/complicaciones , Hepatitis Autoinmune/diagnóstico , Humanos , Hígado/patología , Cirrosis Hepática Biliar/complicaciones , Cirrosis Hepática Biliar/diagnóstico , Masculino , Persona de Mediana Edad , Mitocondrias Hepáticas/inmunología , Pronóstico , Radiografía Abdominal , Estudios Retrospectivos , Síndrome , Adulto JovenRESUMEN
Autoimmune hepatitis (AIH) is a chronic progressive hepatitis, characterized by interface hepatitis with lymphoplasmacellular infiltrates on liver biopsy, high serum globulin level and circulating autoantibodies. It is classified into two types, according to autoantibody profile: type 1 is characterized by anti-nuclear (ANA) and/or anti-smooth muscle (SMA) antibodies; type 2 by anti-liver kidney microsomal type 1 (anti-LKM-1) antibodies. AIH affects all ages, may be asymptomatic, frequently has an acute onset, and can present as fulminant hepatitis. The diagnosis of AIH is based on a scoring system codified by an international consensus. Corticosteroids alone or in conjunction with azathioprine is the treatment of choice in patients with AIH and results in remission induction in over 80% of patients. Alternative proposed strategies in patients who have failed to achieve remission on standard therapy or patients with drug toxicity include the use of cyclosporine, tacrolimus, budesonide or mycophenolate mofetil. Liver transplantation is the treatment of choice in managing decompensated disease, however AIH can recur or develop de novo after liver transplantation.
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Hepatitis Autoinmune/diagnóstico , Hepatitis Autoinmune/terapia , Animales , Hepatitis Autoinmune/tratamiento farmacológico , Hepatitis Autoinmune/inmunología , Humanos , Inmunosupresores/efectos adversos , Inmunosupresores/química , Inmunosupresores/inmunología , Inmunosupresores/uso terapéuticoRESUMEN
BACKGROUND: Population-based studies of the natural course of chronic viral liver disease that consider comorbidity factors are lacking. Using data from the Dionysos Study, we quantified the burden of chronic viral liver disease and the role of alcohol intake to morbidity and mortality in a representative sample of subjects from the general population of two communities of Northern Italy. METHODS AND FINDINGS: We followed up 139 subjects with chronic hepatitis C virus (HCV) infection and 61 with chronic hepatitis B virus (HBV) infection for a median (IQR) time of 8.4 (1.0) and 8.3 (0.9) yr, respectively. Ethanol intake was evaluated using a food-frequency questionnaire, fatty liver (FL) was diagnosed by ultrasonography, and liver cirrhosis (LC) and hepatocarcinoma (HCC) were diagnosed by liver biopsy. Exact multivariable Poisson regression was performed to identify predictors of death. The incidence and remission rates of FL were 9.0 and 29.7 in the HCV cohort and 4.0 and 30.4 per 1,000 person-years (PY) in the HBV cohort. Progression to LC and HCC was more common in the HCV than in the HBV cohort (4.5 vs 2.0 and 2.7 vs 2.0 per 1,000 PY, respectively). Ethanol intake was an independent predictor of LC in the HCV cohort [rate ratio (RR) = 4.15 (95% CI 1.02-41.2) for every increase of 30 g/day of ethanol intake at baseline] and of death rate in both cohorts [RR = 8.53 (95% CI 1.40-24.61) and 3.56 (1.34 to 26.50) for every increase of 30 g/day of ethanol intake at baseline]. CONCLUSIONS: The morbidity and mortality rate of HBV and HCV infection in the general population is lower than that reported in secondary-care populations, blood donors, or clinical series. Ethanol intake is an independent predictor of LC in subjects with chronic HCV infection and an independent predictor of death in subjects with either HCV or HBV infection.
Asunto(s)
Consumo de Bebidas Alcohólicas , Hepatitis B/mortalidad , Hepatitis C Crónica/mortalidad , Adolescente , Adulto , Anciano , Causas de Muerte , Niño , Femenino , Humanos , Incidencia , Italia/epidemiología , Masculino , Persona de Mediana Edad , Distribución de Poisson , Prevalencia , ARN Viral/análisis , Estadísticas no Paramétricas , Encuestas y CuestionariosRESUMEN
The current epidemic of non-alcoholic fatty liver disease (NAFLD) is reshaping the field of hepatology all around the world. The widespread diffusion of metabolic risk factors such as obesity, type2-diabetes mellitus, and dyslipidemia has led to a worldwide diffusion of NAFLD. In parallel to the increased availability of effective anti-viral agents, NAFLD is rapidly becoming the most common cause of chronic liver disease in Western Countries, and a similar trend is expected in Eastern Countries in the next years. This epidemic and its consequences have prompted experts from all over the word in identifying effective strategies for the diagnosis, management, and treatment of NAFLD. Different scientific societies from Europe, America, and Asia-Pacific regions have proposed guidelines based on the most recent evidence about NAFLD. These guidelines are consistent with the key elements in the management of NAFLD, but still, show significant difference about some critical points. We reviewed the current literature in English language to identify the most recent scientific guidelines about NAFLD with the aim to find and critically analyse the main differences. We distinguished guidelines from 5 different scientific societies whose reputation is worldwide recognised and who are representative of the clinical practice in different geographical regions. Differences were noted in: the definition of NAFLD, the opportunity of NAFLD screening in high-risk patients, the non-invasive test proposed for the diagnosis of NAFLD and the identification of NAFLD patients with advanced fibrosis, in the follow-up protocols and, finally, in the treatment strategy (especially in the proposed pharmacological management). These difference have been discussed in the light of the possible evolution of the scenario of NAFLD in the next years.
Asunto(s)
Diabetes Mellitus Tipo 2/complicaciones , Medicina Basada en la Evidencia/normas , Hígado/patología , Enfermedad del Hígado Graso no Alcohólico/terapia , Obesidad/complicaciones , Consumo de Bebidas Alcohólicas/efectos adversos , Cirugía Bariátrica/normas , Biopsia , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/epidemiología , Medicina Basada en la Evidencia/métodos , Fibrosis , Salud Global , Humanos , Hipoglucemiantes/normas , Hipoglucemiantes/uso terapéutico , Hígado/diagnóstico por imagen , Hígado/efectos de los fármacos , Hígado/cirugía , Pruebas de Función Hepática , Trasplante de Hígado/normas , Imagen por Resonancia Magnética , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Enfermedad del Hígado Graso no Alcohólico/etiología , Obesidad/epidemiología , Obesidad/cirugía , Guías de Práctica Clínica como Asunto , Prevalencia , Sustancias Protectoras/normas , Sustancias Protectoras/uso terapéutico , Factores de Riesgo , UltrasonografíaRESUMEN
One of the first stages of apoptosis is cytokeratin cleavage mediated by caspases, which is associated with the expression of a neoepitope, the cleavage site of cytokeratin 18, identifiable by the M30 monoclonal antibody. The aim of this study was to evaluate the timing of neoantigen expression and its modifications in the various morphologic stages of apoptosis on frozen and paraffin-embedded sections from liver biopsies of patients with chronic hepatitis or transplanted liver. The appearance of this neoepitope coincides with the gradual disappearance of cytokeratins, with the appearance of nuclear DNA fragmentation, and with the presence of Councilman bodies. The staining patterns on paraffin-embedded sections of liver specimens were similar to those found in frozen sections, with a reduced sensitivity. The M30 antibody is correlated with apoptosis, and its specificity for epithelial cells makes this method the first choice for routine evaluation of apoptosis in liver epithelial cells.
Asunto(s)
Fragmentación del ADN , Hepatocitos/metabolismo , Queratinas/metabolismo , Hígado/metabolismo , Hígado/patología , Anticuerpos Monoclonales , Biomarcadores/análisis , Núcleo Celular/metabolismo , Núcleo Celular/patología , Citoplasma/metabolismo , Citoplasma/patología , Mapeo Epitopo , Técnica del Anticuerpo Fluorescente Indirecta , Secciones por Congelación , Hepatitis Crónica/metabolismo , Hepatitis Crónica/patología , Hepatocitos/patología , Humanos , Etiquetado Corte-Fin in Situ , Queratinas/inmunología , Trasplante de Hígado , Adhesión en ParafinaRESUMEN
BACKGROUND: Hepatitis C virus infection frequently leads to chronic hepatitis, possibly evolving to end-stage liver disease and hepatocellular carcinoma. Regulatory T cells can affect antiviral immune response thus influencing the outcome of the disease. AIM: To determine numeric and functional distribution of regulatory T cells expressing CD4+CD25hiFoxp3+ (T-regs) during the different stages of hepatitis C virus-related liver disease. METHODS: 90 hepatitis C viraemic patients and 50 healthy controls were included. Surface and intracellular (Foxp3) T-reg markers were evaluated by flow cytometry. Target cell proliferation and interferon-gamma production were evaluated in 37 HCV patients. In 16 cases intrahepatic distribution of Foxp3 by immuno-histochemistry was assessed. RESULTS: T-regs were increased in hepatitis C virus infected patients and correlated inversely with aminotransferases and directly with MELD score and disease duration. A preserved inhibitory ability of interferon-gamma production was distinctive of patients with normal aminotransferases. Circulating T-regs did not correlate with intrahepatic distribution of Foxp3. CONCLUSIONS: In chronic hepatitis C, selective expansion of peripheral T-regs in patients with normal aminotransferases and advanced disease suggests that, though a continual low level inflammation does not prevent liver disease progression, once cirrhosis has developed it may represent an attempt to prevent immuno-mediated decompensation.