Autoimmune and non-autoimmune thyroid dysfunction in HCV infected and HCV-HIV co-infected patients before and after interferon alpha therapy: A prospective study / Disfunción tiroidea autoinmune y no autoinmune en pacientes monoinfectados con VHC y coinfectados con VIH, antes y después del tratamiento con interferón alfa: un estudio prospectivo

INTRODUCTION: Autoimmune thyroid diseases are reported in no treated hepatitis C virus (HCV) infection. The standard interferon alpha (IFNΑ) treatment is associated with an increase of thyroid damage and dysfunction. The present cohort prospective study compared thyroid function and autoimmunity in HCV patients' monoinfected and coinfected HCV-HIV at baseline, during and after IFNΑ therapy. METHODS: We studied 790 HCV infected patients: G1 (monoinfected HCV: N = 580) and G2 (HCV-HIV coinfected: N = 210). They were evaluated for thyroid function and thyroid tiroperoxidase antibodies (TPOAb) at baseline and 235 patients (G1: 183; G2: 52) post IFNΑ therapy. If thyroid dysfunction (TD) was diagnosed, they were reevaluated at 12 month after discontinuation to determine whether the TD was transitory or definitive. RESULTS: No difference was found in the prevalence of TD at baseline in G1 (7.6%) and G2 (9%). However, monoinfected patients showed a higher prevalence of TPOAb positivity with a women preponderance in this group. There was no difference in TD between both groups during IFNΑ therapy (G1 23.5% vs G2 19.2%). In G1 the autoimmune TD was higher than in G2 (67.4% vs 30%, p = 0.02). Autoimmune TD during IFNΑ tended to evolve to definitive hypothyroidism and non-autoimmune TD recovered euthyroidism after IFN #913; discontinuation. The presence of positive TPOAb (RR 3.55) and female gender (RR 2.4) were associated with the development of TD with IFNΑ therapy. CONCLUSIÓN: Our hypothesis is the importance of HCV in G1 and G2, combined with IFNΑ in triggering TD and TPOAb positivity, not described in other diseases' applications

INTRODUCCIÓN: El presente estudio prospectivo de cohorte evaluó y comparó la función y la autoinmunidad tiroidea en pacientes con virus de la hepatitis C (VHC) monoinfectados y coinfectados con VHC-virus de la inmunodeficiencia humana (VIH) al inicio, durante y después de la terapia estándar con interferón alfa (IFNΑ). MÉTODOS: Se estudiaron 790 pacientes infectados por VHC: G1 (VHC monoinfectados: N = 580) y G2 (coinfección por VHC-VIH: N = 210). Se evaluó la función tiroidea y los anticuerpos anti-tiroperoxidasa (ATPO) al inicio del estudio, y a 235 pacientes tratados con IFNΑ (G1: 183; G2: 52). Si se diagnosticó disfunción tiroidea (DT), estos fueron reevaluados 12 meses posteriores al tratamiento para determinar si esta era transitoria o definitiva. RESULTADOS: No se encontraron diferencias en la prevalencia de DT en forma basal G1 (7,6%) vs. G2 (9%). Los pacientes monoinfectados mostraron una mayor prevalencia de positividad de ATPO, siendo preponderante el sexo femenino en el G1. No hubo diferencias en la DT entre ambos grupos con IFNΑ (G1 23,5 vs. G2 19,2%). En G1, la DT autoinmune fue mayor que en G2 (67,4 vs. 30%; p = 0,02). La DT autoinmune con IFNΑ tendió a evolucionar hacia un hipotiroidismo definitivo, mientras que la DT no autoinmune fue transitoria. Tuvieron mayor riesgo de DT durante el tratamiento los pacientes que presentaban ATPO positivos previos (RR: 3,55) y el sexo femenino (RR: 2,4). CONCLUSIONES: Planteamos como hipótesis la importancia del VHC en G1 y G2, combinado con IFNΑ en el desarrollo de la DT y positividad de los ATPO, no descripta en su uso en otras enfermedades

Autoimmune and non-autoimmune thyroid dysfunction in HCV infected and HCV-HIV co-infected patients before and after interferon alpha therapy: A prospective study.

INTRODUCTION: Autoimmune thyroid diseases are reported in no treated hepatitis C virus (HCV) infection. The standard interferon alpha (IFNα) treatment is associated with an increase of thyroid damage and dysfunction. The present cohort prospective study compared thyroid function and autoimmunity in HCV patients' monoinfected and coinfected HCV-HIV at baseline, during and after IFNα therapy. METHODS: We studied 790 HCV infected patients: G1 (monoinfected HCV: N=580) and G2 (HCV-HIV coinfected: N=210). They were evaluated for thyroid function and thyroid tiroperoxidase antibodies (TPOAb) at baseline and 235 patients (G1: 183; G2: 52) post IFNα therapy. If thyroid dysfunction (TD) was diagnosed, they were reevaluated at 12 month after discontinuation to determine whether the TD was transitory or definitive. RESULTS: No difference was found in the prevalence of TD at baseline in G1 (7.6%) and G2 (9%). However, monoinfected patients showed a higher prevalence of TPOAb positivity with a women preponderance in this group. There was no difference in TD between both groups during IFNα therapy (G1 23.5% vs G2 19.2%). In G1 the autoimmune TD was higher than in G2 (67.4% vs 30%, p=0.02). Autoimmune TD during IFNα tended to evolve to definitive hypothyroidism and non-autoimmune TD recovered euthyroidism after IFNα discontinuation. The presence of positive TPOAb (RR 3.55) and female gender (RR 2.4) were associated with the development of TD with IFNα therapy. CONCLUSION: Our hypothesis is the importance of HCV in G1 and G2, combined with IFNα in triggering TD and TPOAb positivity, not described in other diseases' applications.

Clinical epidemiology of acute hepatitis C in South America.

There is scarce data pertaining to acute hepatitis C (aHC) infection in South America. We aimed to describe clinical characteristics and evolution of aHC in a South American cohort. A retrospective survey was conducted at 13 hepatology units. All patients ≥16 years old with aHC diagnosis were included. Demographic, clinical and outcome information were registered in a standardized ad hoc questionnaire. Sixty-four patients were included. The majority were middle-aged (median age: 46 years) and female (65.6%); most of them were symptomatic at diagnosis (79.6%). HCV-1 was the most prevalent genotype (69.2%). Five patients had liver failure: three cases of severe acute hepatitis, one case of fulminant hepatitis and one case of acute-on-chronic liver failure. Nosocomial exposure was the most prevalent risk factor. Evolution was assessed in 46 patients. In the untreated cohort, spontaneous resolution occurred in 45.8% and was associated with higher values of AST/ALT and with the absence of intermittent HCV RNA viremia (P = 0.01, 0.05, and 0.01, respectively). In the treated cohort, sustained virological response was associated with nosocomial transmission and early treatment initiation (P = 0.04 each). The prevalence of nosocomial transmission in this South-American cohort of aHC stresses the importance of following universal precautions to prevent HCV infection. J. Med. Virol. 89:276-283, 2017. © 2016 Wiley Periodicals, Inc.

Inkjet printed periodical micropatterns made of inert alumina ceramics induce contact guidance and stimulate osteogenic differentiation of mesenchymal stromal cells.

Bioinert high performance ceramics exhibit detrimental features for implant components with direct bone contact because of their low osseointegrating capability. We hypothesized that periodical microstructures made of inert alumina ceramics can influence the osteogenic differentiation of human mesenchymal stromal cells (hMSC). In this study, we manufactured pillared arrays made of alumina ceramics with periodicities as low as 100µm and pillar heights of 40µm employing direct inkjet printing (DIP) technique. The response of hMSC to the microstructured surfaces was monitored by measuring cell morphology, viability and formation of focal adhesion complexes. Osteogenic differentiation of hMSCs was investigated by alkaline phosphatase activity, mineralization assays and expression analysis of respective markers. We demonstrated that MSCs react to the pillars with contact guidance. Subsequently, cells grow onto and form connections between the microstructures, and at the same time are directly attached to the pillars as shown by focal adhesion stainings. Cells build up tissue-like constructs with heights up to the micropillars resulting in increased cell viability and osteogenic differentiating properties. We conclude that periodical micropatterns on the micrometer scale made of inert alumina ceramics can mediate focal adhesion dependent cell adhesion and stimulate osteogenic differentiation of hMSCs.

Efficacy and safety of long term entecavir in chronic hepatitis B treatment naïve patients in clinical practice.

BACKGROUND AND AIMS: Entecavir (ETV) is effective and safe in patients with chronic hepatitis B in the short term, but its long term efficacy and safety has not been established. MATERIAL AND METHODS: We evaluated HBV DNA clearance, HBeAg/antiHBe and HBsAg/antiHBs seroconversion rates in HBeAg-positive and negative NUC naïve HBV patients treated with ETV for more than 6 months, and predictors of response. RESULTS: A hundred and sixty nine consecutive patients were treated with ETV for a median of 181 weeks. 61% were HBeAg positive, 23% were cirrhotics, and mean HBV-DNA levels were 6,88 ± 1,74 log10 IU/mL. Overall, 156 (92%) patients became HBV DNA undetectable, 92 (88%) HBeAg positive and 64 (98%) HBeAg negative patients. Seventy four (71%) patients cleared HBeAg after a median of 48 weeks of treatment, 23 (14%) patients cleared HBsAg (19 HBeAg positive and 4 HBeAg negative, p 0.025) after a median of 96 weeks of treatment, and 22 (13%) patients developed protective titers of anti-HBs. At the end of the study, 35 (20%) patients had discontinued therapy: 33 HBeAg positive and 2 HBeAg negative; 9 of them (26%) developed virological relapse after a median of 48 weeks of stopping treatment. None of the patients had primary non response and one patient developed breakthrough. Two patients developed HCC, three underwent liver transplantation and 3 deaths were attributable to liver-related events. No serious adverse events were reported. CONCLUSION: Long term ETV treatment showed high virological response rates, and a favorable safety profile for NUC-naive HBeAg-positive and negative patients treated in clinical practice.

[Idiophatic inflammatory myophaties: its asociation with liver disorders]. / Miopatías inflamatorias idiopática: su asociación a hepatopatías.

UNLABELLED: The aspartate aminotransferase (SGOT) and alanine aminotransferase (SGPT) are sensitive indicators of liver damage. While the TSGOT is also found in other organs, the SGPT is considered an enzyme specific liver. However, some authors state that the TGP can rise also in cases of muscle injury. Furthermore, there are reports in the literature suggesting the association of idiopathic inflammatory myopathies (IIM) with viral hepatitis. OBJECTIVE: To determine the frequency of abnormal liver function tests in patients with idiopathic inflammatory myopathies, evaluate possible associationsto liver diseases, determine its relationship with elevation of muscle enzymes and whether these patients have particular clinical and / or serological characteristics. MATERIAL AND METHODS: Consecutive patients older than 16 years diagnosed with DM / PM according to Bohan and Peter criteria during 1999-2000 were included. Patients with other connective tissue disease (CTD) were excluded. Demographic data were recorded, characteristics of the disease, laboratory data and elevated liver enzymes and muscle during the course of the disease. Serologic tests were performed for viral hepatitis B and C and confirmatory tests (HBV-DNA and HCV-RNA by PCR). Autoantibodies were determined: ANA (antinuclear antibody) by Hep II, ASMA (anti smooth muscle antibody), AMA (anti-mitochondrial antibodies) and LKM (Liver Kidney Microsomal) by mouse wound, MSA (myositis-specific antibodies) by ELISA. Patients who had abnormal liver tests underwent hepatic ultrasonography. For statistical analysis, descriptive statistics, categorical variables were compared by Fisher's exact test. RESULTS: We included 27 patients, of whom 22 had sufficient data for analysis. Mean age 47.95 years ± 16, 18 female (81.8%) and mean disease duration 8.09 ± 5.6 years. With regard to liver enzymes, 14/22 patients (63.3%) had elevated SGPT and 11/22 (50%) elevated SGOT, 10 of these patients also had elevated SGPT concomitantly. In the 10/15 (66.7%) abdominal ultrasonography showed abnormalities, 8 patients had liver hyperechogenicity, 4 cholelithiasis and 1 patient hepatomegaly. No patient bearing of HBV or HCV. The 8 patients with liver hyperechogenicity matched the 8 patients with isolated elevation of SGPT/SGOT. As for the 10 patients who had both elevated liver enzymes (SGPT and SGOT), only one case could be explained by liver disease (patient ASMA +). However in the 15 cases studied, elevations of SGPT and / or SGOT coincided with outbreaks of myositis,findingconcomitant apparent liver disease in only 9 of them. CONCLUSIONS: In this study, elevated transaminases, including the TGP, was observed concomitantly with the activity of myositis. Approximately half of these cases could not be associated with coexisting liver disease, which could be attributed to injury to muscle secondary to inflammatory myopathy.

The most severe forms of type I autoimmune hepatitis are associated with genetically determined levels of TGF-beta1.

We previously reported that paediatric (PAH) and adult (AAH) forms of type I autoimmune hepatitis (AH) have different HLA-associations and clinical outcome. In the present study we investigated the role of TGF-beta1 genetic polymorphisms in the different outcome of PAH and AAH. We found a significant increase of "high producer" 25GG genotype in PAH and 10CC in AAH. Low inflammation and low fibrosis in AAH was associated with the increase of codon 10CC (high producer) and codon 25CC (low producer) genotypes. The analysis in AAH of the two positions-haplotypes revealed that combined presence of 25GG and 10CC seems to neutralize the 10CC effect which remained in AAH having the 10CC(+)-25GG(-) haplotype. Altogether these results may explain, at least partially, the different clinical outcome of AAH and PAH.

Gender susceptibility to chronic hepatitis C virus infection associated with interleukin 10 promoter polymorphism.

Elevated levels of interleukin 10 (IL-10) were previously described for chronically hepatitis C virus (HCV)-infected patients. We determined by a sequence-specific oligonucleotide probing technique the IL-10 promoter genotypes in 286 Argentinean HCV patients grouped according to disease outcome. The GG genotype (position -1082) is known to be associated with high IL-10 production, GA is considered an intermediate producer, and AA is associated with low IL-10 production. We found an increase in frequency of the GG genotype in female patients who do not eliminate the virus (RNA(+)). In these patients, the GG frequency was 0.19, versus 0.10 in controls (P = 0.03). This association became more significant in those RNA(+) female patients with elevated hepatic transaminases (GG frequency of 0.25; P = 0.0013). Additionally, this genotype frequency was higher in noncirrhotic female patients than in controls (GG frequency for noncirrhotic female patients was 0.31; P = 0.009). In RNA(-) patients, the GA frequency was elevated compared with that in controls (GA frequency of 0.76 in RNA(-) patients versus 0.48 in controls; P = 0.01), that in all HCV patients (GA frequency of 0.43; P = 0.001), and that in RNA(+) patients (GA frequency of 0.40; P = 0.0005). We conclude that a gender effect is observed with women carrying the GG high IL-10 producer genotype. The higher levels of IL-10 present in those individuals are associated with a higher risk of an inefficient clearance of the HCV and the development of a chronic HCV infection together with a lower risk of progression to cirrhosis in female patients.

Baja prevalencia de anticuerpos antifosfolípidos autoinmunes en enfermedades hepáticas / Low prevalence of autoimmune antiphospholipid antibodies in hepatic diseases

Antiphospholipid antibodies (aPL) have been associated with different diseases. They are defined as a large family of immunoglobulins (Ig) of either alloantibodies or autoantibodies. The autoimmune antibodies are associated with venous and/or arterial thrombosis, thrombocytopenia and recurrent fetal loss in the so-called antiphospholipid syndrome or in systemic lupus erythematosus. These antibodies are directed against proteins or phospholipid-protein complexes. On the contrary, antiphospholipid antibodies (alloantibodies) which are found in infectious diseases sera (syphilis, HIV, and other viral diseases), disappear with illness remission and are directed to phospholipids alone (particularly cardiolipin) and are not associated with thrombosis or recurrent fetal loss. However, the role and type of aPL found during hepatic diseases is still unclear. To investigate the prevalence of autoimmune aPL (IgG and IgM) during different hepatic diseases, we have studied 128 patients with hepatitis C virus, hepatitis B virus and hepatic autoimmune diseases without treatment as well as 40 healthy control subjects. We have used a specific ELISA kit, that uses a mixture of phospholipid instead of cardiolipin alone, and allows a better detection of aPL of the autoimmune type. Our results show that autoimmune aPL are not significantly increased in viral hepatic diseases (2%) or autoimmune diseases of the liver (3%) when compared to the control group (0%).

Baja prevalencia de anticuerpos antifosfolípidos autoinmunes en enfermedades hepáticas / Low prevalence of autoimmune antiphospholipid antibodies in hepatic diseases

Antiphospholipid antibodies (aPL) have been associated with different diseases. They are defined as a large family of immunoglobulins (Ig) of either alloantibodies or autoantibodies. The autoimmune antibodies are associated with venous and/or arterial thrombosis, thrombocytopenia and recurrent fetal loss in the so-called antiphospholipid syndrome or in systemic lupus erythematosus. These antibodies are directed against proteins or phospholipid-protein complexes. On the contrary, antiphospholipid antibodies (alloantibodies) which are found in infectious diseases sera (syphilis, HIV, and other viral diseases), disappear with illness remission and are directed to phospholipids alone (particularly cardiolipin) and are not associated with thrombosis or recurrent fetal loss. However, the role and type of aPL found during hepatic diseases is still unclear. To investigate the prevalence of autoimmune aPL (IgG and IgM) during different hepatic diseases, we have studied 128 patients with hepatitis C virus, hepatitis B virus and hepatic autoimmune diseases without treatment as well as 40 healthy control subjects. We have used a specific ELISA kit, that uses a mixture of phospholipid instead of cardiolipin alone, and allows a better detection of aPL of the autoimmune type. Our results show that autoimmune aPL are not significantly increased in viral hepatic diseases (2%) or autoimmune diseases of the liver (3%) when compared to the control group (0%). (AU)