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Biomedical subjects

Silvia Fargion

Publications and source records attributed to Silvia Fargion.

At least 19 recordsLinked to original sources
PubMed2006

Triple antiviral therapy in HCV positive patients who failed prior combination therapy.

AIM: To assess the efficacy of triple therapy (peginte-rferon or high dose standard interferon, plus ribavirin and amantadine) in nonresponders to prior combination therapy. METHODS: A total of 196 patients were enrolled in a multicenter, open, randomized study. Patients were given 180 mug/wk of peginterferon-alpha-2a (40 kDa) plus ribavirin (800-1000 mg/d) and amantadine (200 mg/d) for 48 wk (group A) or interferon-alpha-2a (6 MU/d for 4 wk, 3 MU/d for 20 wk, and 3 MU tiw for 24 wk) plus ribavirin (800-1000 mg/d) and amantadine (200 mg/d) for 48 wk (group B). RESULTS: Overall sustained virologic response (SVR) was 26.6% (32.1% and 19.5% in group A and B, P = 0.057). Baseline ALT > 120 UI/L (OR 2.4; 95% CI: 1.11 to 5.20; P = 0.026) and HCV RNA negativity after 12 wk (OR 8.7; 95% CI: 3.87 to 19.74; P < 0.0001) were independently associated with SVR. Therapy discontinuation occurred less frequently in patients treated with peginterferon than standard interferon (P = 0.036). CONCLUSION: More than 25% of nonresponders to combination therapy can eradicate HCV infection when retreated with triple therapy, especially if they have a high baseline ALT and are treated with pegylated interferon.

Adolescent↗
PubMed2006

Alpha 1-antitrypsin mutations in NAFLD: high prevalence and association with altered iron metabolism but not with liver damage.

Hyperferritinemia, a common feature of nonalcoholic fatty liver disease (NAFLD), has been associated with steatohepatitis and fibrosis. Heterozygosity for alpha 1-antitrypsin (AAT) mutations is a cofactor of liver damage, and AAT influences inflammation and iron metabolism. This study evaluated the prevalence of the common AAT PiS/PiZ mutants in 353 patients with NAFLD, 195 of whom had hyperferritinemia, versus 114 matched controls and their influence on iron metabolism and the severity of liver damage in the 212 patients submitted to biopsy. PiS and PiZ alleles were searched for by restriction analysis. Thirty-eight patients (10.8%) carried non-MM genotypes versus 4/114 (3.5%) controls (P = .02). Patients carrying AAT mutations had higher ferritin (573 [454-966] vs. 348 [201-648]; P = .001) with similar transferrin saturation. The difference was more evident in males (P < .0001) and significant in patients not carrying HFE genotypes associated with iron overload (P = .015). The prevalence of non-MM genotypes was higher in patients with hyperferritinemia than in those without (28/195, 14% vs. 10/158, 6%, P = .016), and AAT mutations were associated with higher prevalence of sinusoidal siderosis (17/27, 63% vs. 70/180, 39%; P = .02), and sinusoidal/total iron score (46.3 +/- 38% vs. 25.1 +/- 35%, P = .01). Although ferritin was independently associated with fibrosis (P = .047), AAT mutations favoring sinusoidal iron deposition did not affect liver damage. In conclusion, AAT mutations are associated with hyperferritinemia and sinusoidal iron accumulation, but not with more severe liver damage in NAFLD.

Alleles↗
PubMed2006

Daily dose of interferon alpha-2b and ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection: a randomised controlled study.

OBJECTIVE: The treatment of patients with hepatitis C virus (HCV) genotype 1 infection remains disappointing. METHODS: In 1999, we started a multicentre study comparing two regimens of recombinant interferon (IFN) alpha-2b plus ribavirin. Group A (90 patients) received ribavirin plus IFN alpha-2b 5 MU/day for 1 month (induction therapy) followed by IFN alpha-2b 5 MU thrice weekly for 5 months. Group B (85 patients) received ribavirin plus IFN alpha-2b 5 MU thrice weekly for 6 months. Responders in both arms received IFN alpha-2b 3 MU thrice weekly for a further 6 months. A follow-up evaluation was performed at 18 months. RESULTS: One hundred and seventy-five consecutive treatment-naive patients with HCV genotype 1 infection were enrolled in the study. A sustained virological response (SVR) was obtained in 51 (29%) patients: 28 in group A (31%) and 23 in group B (27%). HCV-RNA clearance was greater at 3 months among patients who received induction therapy (57 vs 39%; p < 0.02). Age, sex, and initial viral load did not influence the achievement of a SVR. HCV clearance at the end of the study was lower in cirrhotic patients (3/26 vs 48/149; p < 0.05). The only SVR in patients with cirrhosis occurred in those from group A (p < 0.05). Both regimens were well tolerated. CONCLUSIONS: This study confirms the low rate of SVR in treatment-naive patients with HCV genotype 1 infection treated with IFN alpha-2b plus ribavirin. A 4-week induction regimen was slightly superior to standard IFN alpha-2b plus ribavirin. Although the number of patients with cirrhosis was low, induction therapy seemed to be more effective in cirrhotics. Given its safety and tolerability, the induction regimen evaluated here may be a therapeutic option in treatment-naive patients with HCV genotype 1 infection.

Adult↗
PubMed2005

TNFalpha genotype affects TNFalpha release, insulin sensitivity and the severity of liver disease in HCV chronic hepatitis.

BACKGROUND/AIMS: TNFalpha induces insulin resistance and promoter polymorphisms of TNFalpha gene affect the release of this cytokine, implicated in the pathogenesis of HCV-related diabetes and fatty liver. The aim was to define whether in patients with HCV chronic hepatitis TNFalpha genotype influences TNFalpha activity, insulin resistance, and the severity of the disease. METHODS: 186 patients, 65% with steatosis, 17% with diabetes. TNFalpha and sTNFR2 were determined by ELISA, insulin resistance by HOMA-R index and TNFalpha -238, -308, and -863 polymorphisms by restriction analysis. RESULTS: TNFalpha, sTNFR2, and insulin resistance were higher in patients than in 89 controls. TNFalpha pathway activity was correlated with LDL cholesterol, steatosis, and insulin resistance, which, in turn, was correlated with the severity of liver damage. Patients subdivided according to TNFalpha genotype significantly differed for TNFalpha release, insulin sensitivity and the prevalence of cirrhosis. The -308 and -238 TNFalpha polymorphisms, characterized by increased promoter activity, were associated with higher TNFalpha activity, insulin resistance and severity of the disease, whereas the -863 polymorphism, characterized by reduced promoter activity, with lower TNFalpha activity, and higher insulin sensitivity. CONCLUSIONS: TNFalpha genotype modulates the activity of the TNFalpha pathway, influences insulin sensitivity and the severity of HCV chronic hepatitis.

Adult↗
PubMed2004

Treatment choices for people infected with HCV.

Hepatitis C virus (HCV) infection is one of the leading causes of liver disease in the world. It is a common cause of cirrhosis and hepatocellular carcinoma (HCC), as well as the most common reason for liver transplantation. Thus, appropriate therapeutic approaches have a strong clinical impact on the morbidity and mortality of HCV-infected patients. In this review we outline the most recent results in the therapy of HCV chronic hepatitis. Patients with the best prognostic factors treated with combination therapy (peginterferon and ribavirin) obtained a sustained response rate of 80-95%. We also provide some hints on the most promising results of the newest therapeutic options, which include molecules that inhibit specific enzymes, such as inhibitors of serine proteases, which are now in preclinical or early phase human trials. Host factors influencing the rate of response are also outlined.

Acute Disease↗
PubMed2004

Onset of autoimmune hepatitis during intravenous steroid therapy for thyroid-associated ophthalmopathy in a patient with Hashimoto's thyroiditis: case report.

A 43-year-old woman with Hashimoto's thyroiditis (HT), euthyroid on levothyroxine since 1999, developed thyroid-associated ophthalmopathy (TAO) in February 2002. She had involvement of the eye muscles, as shown by computed tomography (CT) scan. She was started on methylprednisolone pulse therapy 7.5 mg/kg of body weight, (one cycle every 2 weeks, each cycle comprising two infusions on alternate days), with rapid improvement of soft tissue inflammation and of eye motility, as confirmed by the reduction of clinical activity score (CAS) and eye muscles size on CT scan. At the end of treatment the patient showed a marked and rapid increase of serum aminotransferases (up to 1200 U/L). She had negative hepatitis A, B, and C viruses serology, but circulating antinuclear antibodies. A liver biopsy, performed at 4 weeks after the discontinuation of intravenous steroids, led to the diagnosis of autoimmune hepatitis (AIH). The patient was treated with oral steroids with a rapid reduction of serum aminotransferases concentrations. To our knowledge, there have been only two reports of liver dysfunction after intravenous steroids for TAO, but the etiology of such hepatitis had not been established. AIH may develop in patients with multiple autoimmunity and may not become overt until immune rebound occurs (i.e. after cessation of or between immunosuppressive treatment cycles). Steroids are the first line of treatment for AIH, hence their use would not be contraindicated when patients with TAO have chronic hepatitis, provided that the modalities of treatment are appropriate.

Acute Disease↗
PubMed2004

TNFalpha promoter polymorphisms.

Polymorphisms in the promoter of the tumor necrosis factor alpha (TNFalpha) gene have been reported to affect the transcription rate and the release of this cytokine. Among the best studied, the -238 and -308 polymorphisms have been associated with an increased transcriptional activity and TNFalpha release, whereas the -863 polymorphism have been associated with a reduced transcriptional activity. A growing body of evidence indicates that these polymorphisms may affect susceptibility to different diseases. Here we describe a method to detect the -238, -308, and -863 TNFalpha polymorphisms by the polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. Briefly, DNA is amplified by PCR using mutagenic primers containing a single base-pair mismatch adjacent to the polymorphic site to introduce a restriction site into the wild-type nucleotide sequences after amplification. The PCR products are then digested with specific restriction enzymes and analyzed by agarose gel electrophoresis.

Alleles↗
PubMed2003

Sustained response to combination therapy in patients with chronic hepatitis C who failed to respond to interferon.

BACKGROUND/AIMS: The best treatment for chronic hepatitis C patients who do not respond to interferon is still unknown. Reported rates of response to treatment vary as the result of heterogeneous definitions of non-responders and small study size. METHODS: One hundred nineteen hepatitis C virus (HCV) RNA-positive non-responders to high-dose interferon monotherapy received alpha-interferon, 5 MU tiw plus oral ribavirin, 1000-1200 mg/day for 48 weeks (Group A, n=74) or alpha-interferon, 5 MU daily for 4 weeks, followed by 5 MU tiw plus oral ribavirin, 1000-1200 mg/day for 44 weeks (Group B, n=45) according to the Institution where they were followed. Persistently normal alanine aminotransferase and negative HCV RNA up to 72 weeks from treatment onset defined a sustained response. RESULTS: Eighteen patients discontinued treatment (13 developed anemia, two mucositis, one granulocytopenia; two were dropouts), none for serious adverse events. There were 24 (20%) sustained responders, with similar final response rates in Groups A and B. Sustained response was more frequent in patients aged </=40 years (36% vs. 13%; P=0.006) and in those with non-1 genotype (44% vs. 14%; P=0.002). Among genotype 1 patients, the younger ones showed higher response rates (32% vs. 7%; P=0.005). Compared with patients harboring non-1 genotypes, the odds ratio of being a non-responder was 1.68 (confidence interval (CI): 0.53-5.37; P=0.381) in younger genotype 1 patients and 9.53 (CI: 2.84-32; P<0.001) in older genotype 1 patients. CONCLUSIONS: Chronic hepatitis C patients who are non-responders to interferon monotherapy and infected by non-1 genotypes should undergo re-treatment with combination therapy. Treatment should be extended to younger genotype 1 patients who are more susceptible to liver disease worsening because of longer life expectancy and have a higher probability of being long lasting responders than their older counterparts.

Adult↗
PubMed2003

Impact of large regenerative, low grade and high grade dysplastic nodules in hepatocellular carcinoma development.

BACKGROUND/AIMS: The natural outcome of ultrasound-detected macronodules in cirrhosis is still poorly understood. In this study we assessed the incidence and predictors of malignant transformation in a prospective study of 90 consecutive ultrasound-detected macronodules in cirrhosis. METHODS: Macronodules classification was based on recently proposed histological criteria. Extranodular large (LCC) and small cell changes were also evaluated. The follow-up included ultrasound and serum alfa-fetoprotein determination every 3 months. Independent predictors of hepatocellular carcinoma were evaluated by Cox proportional hazards regression analysis. RESULTS: During a mean follow-up of 33 months, 28 (31%) nodules transformed into hepatocellular carcinoma. The incidence of hepatocellular carcinoma per 100 person-years of follow-up was 11.3%, with a malignant transformation rate of 3.5, 15.5, 31 and 48.5% at 1, 2, 3, and 5 years respectively. High-grade dysplastic nodules (HGDN) (hazard risk=2.4; CI 95%=1.1-5.0) and LCC (hazard risk=3.1; CI 95%=1.2-7.8) were independent predictors of malignant transformation. Eight additional hepatocellular carcinomas developed outside the original lesions raising the overall malignant transformation rate to 40% while 15 macronodules (17%) became undetectable at ultrasound (US). CONCLUSIONS: Macronodules characterize a cirrhotic subpopulation with high risk of hepatocellular carcinoma. HGDN and LCC are strong predictors of malignant transformation; subjects with simultaneous presence of both these two conditions are at highest risk of cancer development. The management of cirrhotics with macronodules should be based on morphologic features detected on liver microsamples.

Adult↗
PubMed2003

Mutations of the hemochromatosis gene in Italian candidate blood donors with increased transferrin saturation.

The aim of this study was to analyze the role of HFE mutations in blood donors with iron parameters suggesting iron overload, taking into account the regional distribution of HFE mutations in Italy. We studied 5880 subjects undergoing evaluation for blood donation eligibility, from different areas of Italy. Abnormal iron parameters were defined as transferrin saturation (TS) >50% or >45% and serum ferritin (SF) >300 or >250 microg/ml in males and females, respectively. Subjects with increased TS and/or SF were re-tested and typed for HFE mutations C282Y and H63D. A total of 548 individuals had increased iron parameters at first testing. In total, 179/548 were available for retesting, and in 109 increased TS and/or SF were confirmed. Increased TS was confirmed in 25 individuals, among whom three were C282Y homozygotes and six were compound heterozygotes for C282Y and H63D. Increased TS was more frequent in northern Italy than in southern regions. In individuals with increased TS and/or SF, the frequency of C282Y and H63D was 0.13 and 0.21 in northern-Italy versus 0.05 and 0.45 in southern Italy (P=0.004 for H63D). Nine out of 10 individuals carrying hemochromatosis-associated genotypes (including compound heterozygosity for C282Y and H63D) originated from northern regions. Among controls, the allelic frequencies of C282Y and H63D were 0.037 and 0.16 in the northern regions and 0.015 and 0.16 in the southern regions. In conclusion, over one-third of individuals with persistently altered TS carried hemochromatosis-associated genotypes, confirming that a diagnostic approach based on TS and genotyping of selected cases may represent a viable screening procedure.

Adolescent↗
PubMed2003

Identification of two novel mutations in the 5'-untranslated region of H-ferritin using denaturing high performance liquid chromatography scanning.

BACKGROUND AND OBJECTIVES: Hereditary hyperferritinemia cataract syndrome is caused by mutations of the iron responsive elements (IREs) of L-ferritin mRNA. These alter the IRE structure and determine L-ferritin upregulation. IREs are located in 5'untranslated regions (5'UTR) of ferritin mRNAs. L-ferritin 5'UTR has been extensively studied and up to 21 different mutations have been identified. Only one mutation has been reported for H-ferritin 5'UTR; this mutation modified IRE structure and was apparently associated with high serum ferritin levels and iron overload. DESIGN AND METHODS: To identify other mutations in H ferritin 5'UTR we developed a fast DNA scanning method based on denaturing high performance liquid chromatography (HPLC). Five artificial DNA mutants were produced in order to validate the analytical conditions of the system for the identification of all mutations by single runs at 68 degrees C. The system was used to screen 660 DNA samples from subjects with high serum ferritin levels. RESULTS: Two abnormal patterns were identified carrying the mutations C20G and G34T. Structural data and the analysis of ferritin levels in red blood cells suggest that these mutations do not affect the functionality of the IRE. INTERPRETATION AND CONCLUSIONS: This large and first population analysis indicates that mutations in the H-ferritin 5'UTR are rare and do not seem to contribute to hyperferritinemia or iron overload.

5' Untranslated Regions↗
PubMed2002

Peripheral lymphocytes and intracellular cytokines in C282Y homozygous hemochromatosis patients.

BACKGROUND/AIMS: Several abnormalities in the immune status of hereditary hemochromatosis patients have been reported. We evaluated the peripheral blood lymphocytes phenotype and cytokine profile of CD8(+) and CD4(+) T cells in C282Y homozygous hereditary hemochromatosis patients compared to control subjects. METHODS: Peripheral blood lymphocytes from 17 asymptomatic patients and 14 control subjects were analyzed. We determined the distribution of lymphocyte subsets and investigated at single-cell level by flow-cytometry the potential of cytokines production. The frequency of cytokine (interferon gamma, tumor necrosis factor alpha, interleukin 2 (IL-2), IL-4, IL-5, IL-10 and IL-13) producing cells was assessed in total T-lymphocytes, CD3(+)CD8(+) and CD3(+)CD4(+) subsets. RESULTS: The patients studied showed a significant decrease of total lymphocyte count, T CD4(+)CD3(+), CD28(+), CD8(+)CD28(+) lymphocytes and natural killer (NK) CD56(+)CD16(+)CD3(-) cells. The reduction of CD28(+) and CD8(+)CD28(+) lymphocyte count was inversely related to transferrin saturation index. An increase in the ability of T-cells to produce all the cytokines studied and a major increase in IL-4 and IL-10 production in the CD3(+)CD8(+) subset was found. Our results demonstrate that activated Th1 and Th2 lymphocytes coexist in the peripheral blood of hereditary hemochromatosis patients and that T-cytotoxic (Tc) 2 subset is more expanded than in control population. CONCLUSIONS: The association of a decreased number of T CD8(+) cytotoxic lymphocytes and NK cells, and the development of Tc2 cells in asymptomatic C282Y homozygous patients represents an imbalance in their immune function that might contribute to the high incidence of hepatocarcinoma.

Adult↗
PubMed2002

Natural history of juvenile haemochromatosis.

Juvenile haemochromatosis or haemochromatosis type 2 is a rare autosomal recessive disorder which causes iron overload at a young age, affects both sexes equally and is characterized by a prevalence of hypogonadism and cardiopathy. Patients with haemochromatosis type 2 have been reported in different ethnic groups. Linkage to chromosome 1q has been established recently, but the gene remains unknown. We report the analysis of the phenotype of 29 patients from 20 families of different ethnic origin with a juvenile 1q-associated disease. We also compared the clinical expression of 26 juvenile haemochromatosis patients with that of 93 C282Y homozygous males and of 11 subjects with haemochromatosis type 3. Patients with haemochromatosis type 2 were statistically younger at presentation and had a more severe iron burden than C282Y homozygotes and haemochromatosis type 3 patients. They were more frequently affected by cardiopathy, hypogonadism and reduced glucose tolerance. In contrast cirrhosis was not statistically different among the three groups. These data suggest that the rapid iron accumulation in haemochromatosis type 2 causes preferential tissue damage. Our results clarify the natural history of the disease and are compatible with the hypothesis that the HFE2 gene has greater influence on iron absorption than other haemochromatosis-associated genes.

Adolescent↗
PubMed2002

Tumor necrosis factor alpha promoter polymorphisms and insulin resistance in nonalcoholic fatty liver disease.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease, which can range from fatty liver alone to nonalcoholic steatohepatitis and cirrhosis, is related to insulin resistance. Tumor necrosis factor alpha (TNF-alpha) may induce insulin resistance, and polymorphisms of its promoter have been associated with an increased release of this cytokine. We analyzed (1) the prevalence of insulin resistance, (2) the prevalence of the 238 and 308 TNF-alpha polymorphisms, and (3) the relationship among TNF-alpha polymorphisms, insulin resistance, and the occurrence of steatohepatitis in 99 patients with nonalcoholic fatty liver diagnosed by ultrasonography and confirmed by histologic analysis in the 53 who underwent biopsy. METHODS: Insulin resistance was evaluated by the homeostatic metabolic assessment insulin resistance indices and TNF-alpha polymorphisms by polymerase chain reaction and restriction fragment length polymorphism analysis. RESULTS: Insulin resistance was detected in almost all of the patients and was more severe in those with steatohepatitis. The prevalence of the 238, but not of the 308, TNF-alpha polymorphism was higher in subjects with nonalcoholic fatty liver than in controls (31% vs. 15%; P < 0.0001), and patients positive for TNF-alpha polymorphisms had higher insulin resistance indices, a higher prevalence of impaired glucose tolerance, and a lower number of associated risk factors for steatosis. CONCLUSIONS: TNF-alpha polymorphisms could represent a susceptibility genotype for insulin resistance, nonalcoholic fatty liver, and steatohepatitis.

Adult↗
PubMed2002

Iron reduction and sustained response to interferon-alpha therapy in patients with chronic hepatitis C: results of an Italian multicenter randomized study.

OBJECTIVES: It has been suggested that iron depletion improves the response to interferon in patients with chronic hepatitis C. We aimed to evaluate whether iron reduction by phlebotomy before interferon improves the rate of virological sustained response in previously untreated noncirrhotic patients. METHODS: One hundred fourteen hepatitis C virus (HCV) RNA positive patients with hepatic iron concentrations of > or =700 microg/g dry wt (men) and > or =500 microg/g dry wt (women), stratified according to HCV genotype and gamma-glutamyltransferase values, were randomly allocated to interferon alone (6 MU three times a week) (group A) or to phlebotomy until iron depletion followed by interferon (6 MU three times a week) (group B). After 4 months dosage was reduced to 3 MU three times a week for another 8 months. RESULTS: Virological sustained response was observed in 25 patients (22%), nine (15.8%, 95% CI = 7.5-27.9) of group A and 16 (28.1%, 95% CI = 17.0-41.6) of group B. At univariate analysis the variables associated with the response were HCV genotypes 2-3, normal gamma-glutamyltransferase, higher levels of baseline ALT, normal ALT values, and negativity for HCV-RNA at the 3rd month of therapy. At multivariate analysis, genotype and ALT levels at enrollment maintained their association with the response. A trend toward a better response to interferon was observed in patients who received phlebotomy (odds ratio = 2.32, 95% CI = 0.96-6.24, p = 0.082). Patients with hepatic iron concentration of < or = 1100 microg/g dry wt had a trend toward a higher rate of virological sustained response (p = 0.059) when submitted to treatment B. CONCLUSION: Iron removal by phlebotomy is able to improve the rate of response to interferon, especially in patients with lower hepatic iron deposits; it could be useful as adjuvant therapy to new therapeutic modalities.

Adult↗
PubMed2002

Levels of uroporphyrinogen decarboxylase (URO-D) in erythrocytes of Italian porphyria cutanea tarda patients.

Porphyria cutanea tarda (PCT) is a human metabolic disorder due to the acquired or genetic impairment of uroporphyrinogen decarboxylase (URO-D) activity, the fifth enzyme of the heme biosynthetic pathway. A classification of inherited and non-inherited forms is based on the enzyme activity levels in red blood cells (RBC). Clinical manifestations of PCT are often precipitated by triggering factors such as alcohol, drug abuse, estrogens, virus infections, hepatotoxic chemicals and hepatic siderosis. We measured URO-D activity in RBC from a large sample of Italian PCT patients in order to define the enzyme activity distribution and to attempt a correlation among activity, risk factors and clinical outcome. Three classes of patients with low, normal and over-normal URO-D activity were defined according to control values. Low URO-D levels were present in 25.8% of patients, suggesting the familial form of PCT (type II). In this group, the outcome of PCT seems to be less influenced by risk factors. Patients with over-normal URO-D activity in RBC deserve further investigation.

Adult↗