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Biomedical subjects

Manuel Romero-Gómez

Publications and source records attributed to Manuel Romero-Gómez.

At least 19 recordsLinked to original sources
PubMed2006

Insulin resistance and hepatitis C.

Insulin resistance is the major feature of the metabolic syndrome and depends on insulin secretion and insulin sensitivity. In chronic hepatitis C, insulin resistance and type 2 diabetes mellitus are more often seen than in healthy controls or chronic hepatitis B patients. Hepatitis C virus (HCV) infection promotes insulin resistance, mainly by increased TNF production together with enhancement of suppressor of cytokine (SOC-3); both events block PI3K and Akt phosphorylation. Two types of insulin resistance could be found in chronic hepatitis C patients: "viral" and "metabolic" insulin resistance. Insulin resistance in chronic hepatitis C is relevant because it promotes steatosis and fibrosis. The mechanisms by which insulin resistance promotes fibrosis progression include: (1) steatosis, (2) hyperleptinemia, (3) increased TNF production, (4) impaired expression of PPARgamma receptors. Lastly, insulin resistance has been found as a common denominator in patients difficult-to-treat like cirrhotics, overweight, HIV coinfected and Afro-American. Insulin resistance together with fibrosis and genotype has been found to be independently associated with impaired response rate to peginterferon plus ribavirin. Indeed, in genotype 1, the sustained response rate was twice (60%) in patients with HOMA < or = 2 than patients with HOMA > 2. In experiments carried out on Huh-7 cells transfected by full length HCVRNA, interferon alpha blocks HCV replication. However, when insulin (at doses of 128 microU/mL, similar that seen in the hyperinsulinemic state) was added to interferon, the ability to block HCV replication disappeared, and the PKR synthesis was abolished. In summary, hepatitis C promotes insulin resistance and insulin resistance induces interferon resistance, steatosis and fibrosis progression.

Antiviral Agents↗
PubMed2006

HLA-C and KIR genes in hepatitis C virus infection.

Natural killer (NK) cells are key components of the innate antiviral immune response. NK cell function is regulated by the interaction of major histocompatibility complex class I molecules with NK inhibitory receptors. The aim of this study was to investigate the role of the HLA-C/KIR pair in hepatitis C virus clearance in our population. A total of 196 hepatitis C virus-infected patients (65 resolved and 131 with persistent infection) were included in the study. Genotyping of HLA-C was carried out using polymerase chain reaction followed by a reverse sequence-specific oligonucleotide probe detection system. NK receptor-specific polymerase chain reaction typing of KIR2DL1, KIR2DL2, and KIR2DL3 was performed on the same patient group. Frequencies of the KIR2DL2 gene and the KIR2DL2/KIR2DL2 genotype were lower among patients with persistent infection (32.3% vs 45.4% among resolved, P = 0.01, OR = 0.57, 95% CI = 0.36-0.91; and 16.2% vs 32.3% among resolved, P = 0.02, OR = 0.41, 95% CI = 0.19-0.87). Nevertheless, the frequency of the KIR2DL3 gene was higher among patients with persistent infection (66.9% vs 54.6% among resolved P = 0.02, OR = 1.68, 95% CI = 1.07-2.65). Trends toward lower frequencies of the HLA-C2C2 genotype and NK-HLA interactions with strong and moderate affinity among the patients with persistent infection were also observed.

Cytotoxicity Tests, Immunologic↗
PubMed2006

Acute hepatitis due to Mycoplasma pneumoniae infection without lung involvement in adult patients.

Mycoplasma pneumoniae has been associated with cholestatic hepatitis in children, while in adults, the lack of liver involvement has been considered as a typical feature of M. pneumoniae infection. Controversial data have been reported about the possibility of liver involvement with M. pneumoniae community-acquired pneumonia. We present two cases of acute hepatitis associated with M. pneumoniae infection without lung involvement.

Acute Disease↗
PubMed2006

Development and validation of two models for early prediction of response to therapy in genotype 1 chronic hepatitis C.

Early prediction of response to therapy in genotype 1 chronic hepatitis C is difficult. Two predictive models, a pretreatment scoring model (PreT-SM) and a fourth week of therapy scoring model (4w-SM) were constructed in a cohort of 104 patients from a single center (estimation cohort) and validated in a cohort of 141 patients from four independent centers (validation cohort). Individual scores were calculated using variables independently associated with sustained virological response (SVR). Baseline viral load, aspartate aminotransferase/alanine aminotransferase ratio, serum cholesterol, and a numerical score for noninvasive estimation of liver fibrosis were included in the PreT-SM; HCV RNA clearance and PreT-SM scores were included in the 4w-SM. Receiver operating characteristic analysis revealed the area under the curve in the estimation cohort and in the validation cohort to be, respectively, 0.856 and 0.847 for the PreT-SM and 0.908 and 0.907 for the 4w-SM. Low scores were associated with SVR, high scores with non-SVR. The best cutoff scores from the PreT-SM (7 and 9.70) identified, respectively, 36% of patients with SVR and 41% of those with non-SVR from the validation cohort, with high accuracy (> or =90% positive predictive value [PPV] and specificity). Similarly, cutoff scores of 3.20 and 5.60 from the 4w-SM identified, respectively, 71% of patients with SVR and 53% of those with non-SVR from the same cohort with high accuracy (PPV and specificity >92%). In conclusion, these models predicted response to therapy before or after 4 weeks of treatment in approximately 60% of genotype 1 patients and may be valuable for the management of this condition.

Adult↗
PubMed2006

Peginterferon-alfa2a plus ribavirin for 48 versus 72 weeks in patients with detectable hepatitis C virus RNA at week 4 of treatment.

BACKGROUND & AIMS: Patients with chronic hepatitis C who do not respond rapidly to therapy have a low chance of developing a sustained virologic response (SVR) when treated for 48 weeks. This study investigated whether treatment for 72 weeks increases the rate of SVR in patients with detectable hepatitis C virus (HCV)-RNA levels at week 4 of treatment. METHODS: A total of 510 treatment-naive patients were treated with peginterferon-alfa2a (180 microg/wk) plus ribavirin (800 mg/day). Patients with detectable HCV-RNA levels at week 4 (n = 326) were randomized to complete 48 (group A, n = 165) or 72 weeks (group B, n = 161) of treatment. Patients with undetectable HCV-RNA levels at week 4 (n = 184) were allocated into group C (n = 148) or group D (n = 36), according to HCV genotype and baseline viremia, and treated for 24 or 48 weeks, respectively. All patients were followed-up for 24 weeks after the end of treatment. RESULTS: The end-of-treatment response rate (61%) was similar in groups A and B, but the SVR rate was higher in group B (45% vs 32% in A; P = .01). In genotype 1-infected patients randomized to group A (n = 149) or B (n = 142), SVR rates were 28% and 44%, respectively (P = .003). The incidence of adverse events was similar in all groups. Treatment discontinuation was more frequent in group B (36%) than in group A (18%) (P = .0004). SVR rates in groups C and D were 79% and 64%, respectively. CONCLUSIONS: Extension of treatment with peginterferon-alfa2a plus ribavirin from 48 to 72 weeks significantly increases the rate of SVR in patients with detectable viremia at week 4 of treatment.

Adult↗
PubMed2006

Incidence of and factors associated with hepatocellular carcinoma among hepatitis C virus and human immunodeficiency virus coinfected patients with decompensated cirrhosis.

We compared the incidence of and factors associated with hepatocellular carcinoma (HCC) among hepatitis C virus (HCV)-monoinfected subjects and human immunodeficiency virus (HIV)/HCV-coinfected individuals, both with decompensated cirrhosis. In a retrospective study, a cohort of 180 individuals with HIV coinfection and 1037 HCV-monoinfected patients with decompensated HCV-related cirrhosis from eight centres in Spain were analyzed. HCC was found in 234 (23%) HCV-monoinfected subjects and in four (2%) HIV-coinfected subjects (p<0.001). At the time of the first hepatic decompensation, 188 (17%) and 4 (2%) (p<0.001) patients in the former and in the latter group, respectively, showed HCC. Fifty-four (11%) patients without HCC at baseline developed such a disease during follow-up. There were no incident cases among the HIV-coinfected population. The density of incidence (95% IC) of HCC in HIV/HCV-coinfected and HCV-monoinfected patients was 0 (0-1.70) and 3.31 (2.70-4.64) cases per 100 person-years (p<0.001), respectively. Lack of HIV infection [adjusted odds risk (AOR) (95% IC)=16.7 (3.9-71.1)] and high alanine aminotransferase levels [AOR (95% IC)=2.5 (1.1-5)] were the only two independent predictors of the emergence of HCC. In the group of patients in whom the date of HCV infection could be estimated, the time elapsed until HCC diagnosis was shorter among HIV-coinfected subjects. The incidence of HCC in patients with HCV-related cirrhosis after the first hepatic decompensation is lower in HIV-coinfected patients. This is probably due to the fact that HIV infection shortens the survival of HCV-coinfected patients with end-stage liver disease to such an extent that HCC not had a chance to emerge.

Aged↗
PubMed2005

HIV coinfection shortens the survival of patients with hepatitis C virus-related decompensated cirrhosis.

The impact of human immunodeficiency virus (HIV) coinfection on the survival of patients with hepatitis C virus (HCV)-related end-stage liver disease (ESLD) is unknown. Because HIV infection is no longer considered an absolute contraindication for liver transplantation in some countries, it has become a priority to address this topic. The objective of this study was to compare the survival of HIV-infected and HIV-uninfected patients with decompensated cirrhosis due to HCV. In a retrospective cohort study, the survival of 1,037 HCV monoinfected and 180 HCV/HIV-coinfected patients with cirrhosis after the first hepatic decompensation was analyzed. Of the group, 386 (37%) HCV-monoinfected and 100 (56%) HCV/HIV-coinfected subjects died during the follow-up. The median survival time of HIV-infected and HIV-uninfected patients was 16 and 48 months, respectively (P < .001). The relative risk (95% CI) of death for HIV-infected patients was 2.26 (1.51-3.38). Other independent predictors of survival were age older than 63 years (2.25 [1.53-3.31]); Child-Turcotte-Pugh class B versus class A (1.95 [1.41-2.68]) and class C versus class A (2.78 [1.66-4.70]); hepatitis D virus infection (1.56 [1.12-4.77]); model for end-stage liver disease score, (1.05 [1.01-1-11]); more than one simultaneous decompensation (1.23 [1.12-3.33]); and the type of the first hepatic decompensation, with a poorer prognosis associated with encephalopathy compared with portal hypertensive gastrointestinal bleeding (2.03 [1.26-3.10]). In conclusion, HIV coinfection reduces considerably the survival of patients with HCV-related ESLD independently of other markers of poor prognosis. This fact must be taken into account to establish the adequate timing of liver transplantation in HIV-coinfected subjects.

Adult↗
PubMed2005

Role of phosphate-activated glutaminase in the pathogenesis of hepatic encephalopathy.

Disturbed body nitrogen homeostasis due to impaired hepatic urea synthesis leads to an alteration in inter-organ ammonia trafficking, resulting in hyperammonemia. Glutamine (Gln) synthase is the alternative pathway for ammonia detoxification. Gln taken up by several organs is split by the intramitochondrial phosphate-activated enzyme glutaminase (PAG) into glutamate (Glu) and ammonia. In cirrhotic patients with portosystemic intrahepatic shunt, the main source of systemic hyperammonemia is the small intestine, and ammonia derives mainly from Gln deamidation. Recently, PAG has been found increased in cirrhotics showing minimal hepatic encephalopathy and, therefore, could be implicated in the production of systemic hyperammonemia in these patients. Intestinal PAG activity correlates with psychometric test and magnetic resonance spectroscopy findings. Moreover, nitric oxide and tumor necrosis factor seem to be the major factors regulating intestinal ammonia production in cirrhotics. In the brain, PAG localized into the astrocytes is responsible for ammonia and free-radical production. The blockade of PAG, using 6-oxo-5-norleucine, avoids the toxic effects of Gln accumulation in the brain. These data support an important role for intestinal and brain glutaminase in the pathogenesis of hepatic encephalopathy and could be a new target for future therapies.

Animals↗
PubMed2005

Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients.

BACKGROUND & AIMS: We evaluated the effect of insulin resistance and viral factors on sustained virological response in patients with chronic hepatitis C treated with peginterferon plus ribavirin. METHODS: Patients (n=159; 94 men; age, 41.7 +/- 11.1 years) with chronic hepatitis C (genotype 1, n=113; non-1 genotype, n=46) received treatment with interferon plus ribavirin. Serum levels of leptin and insulin were measured, and the insulin resistance index (HOMA-IR: homeostasis model of assessment) and body mass index were calculated. RESULTS: A sustained virological response was associated with lower age, insulin resistance index, body mass index, and gamma-glutamyltranspeptidase and serum leptin levels. There was no association with viral load, sex, type of interferon, or cholesterol levels. A sustained virological response was achieved in 43.4% (46/113) of genotype 1 and 89% (32/36) of genotype 2 and 3 (P=.0001) patients. Necroinflammatory activity and steatosis were not associated with the sustained virological response rate. Multivariate regression analysis indicated that the independent variables related to sustained virological response were genotype (odds ratio, 3.57; 95% confidence interval, 1.49-8.3; P=.001), insulin resistance index (odds ratio, 1.82; 95% confidence interval, 1.08-3.06; P=.012), and fibrosis (odds ratio, 1.36; 95% confidence interval, 1.01-1.84; P=.029). A sustained virological response in patients with genotype 1 and insulin resistance (HOMA-IR > 2) occurred in 23 of 70 (32.8%; 95% confidence interval, 21.9%-43.9%) patients, vs. 26 of 43 (60.5%; 95% confidence interval, 45.9%-75.1%) genotype 1 patients without insulin resistance (P=.007; odds ratio, 3.12, 95% confidence interval, 1.42-6.89). CONCLUSIONS: Insulin resistance, fibrosis, and genotype are independent predictors of the response to antiviral therapy in chronic hepatitis C patients treated with peginterferon plus ribavirin.

Adult↗
PubMed2004

Prognostic value of altered oral glutamine challenge in patients with minimal hepatic encephalopathy.

Oral glutamine challenge (OGC) has been found to be safe, and an altered response predicts elevated risk of overt hepatic encephalopathy (HE) in patients with minimal hepatic encephalopathy (MHE). We assessed the survival prognosis of patients with cirrhosis, but without current overt HE, who have an altered OGC and MHE. MHE was inferred using 3 neuropsychological tests. Venous ammonia concentrations were measured pre- and post-60 minutes of a 10 g oral glutamine load. The median follow-up was 25.2 months, by which time 22 patients had had bouts of overt HE and 18 had died from liver-related causes. The results in 126 patients with cirrhosis, indicated 25 with MHE and abnormal OGC response. Survival among patients who developed overt HE was 59% at 1 year and 38% at 3 years. In patients without HE, survival was 96% and 86% at 1 and 3 years, respectively (log-rank 50.9, P <.0001). The presence of MHE was not related to survival (log-rank 2.21, P =.23). Patients with MHE and abnormal OGC test had elevated mortality risk (log-rank 13.1, P =.0003). Multivariate analyses indicated Child-Pugh score (hazard ratio [HR] 1.46; 95% CI, 1.46-2.08), and MHE plus altered OGC response (HR 5.5; 95% CI, 1.81-16.6) were predictors of mortality, whether from liver-related or non-liver-related causes. In conclusion, a pathological OGC response in patients with MHE appears to be associated with lower survival rate and may prove useful in the selection of candidates for liver transplantation.

Administration, Oral↗
PubMed2004

Intestinal glutaminase activity is increased in liver cirrhosis and correlates with minimal hepatic encephalopathy.

BACKGROUND/AIMS: We performed the current study to assess the intestinal activity of enterocyte phosphate-activated glutaminase (PAG) in cirrhosis. METHODS: Forty-nine cirrhotic patients and 36 control subjects underwent endoscopic duodenal biopsies. Minimal hepatic encephalopathy (MHE) was evaluated using three psychometric tests. Oral glutamine challenge (OGC) was performed and MELD, Child-Pugh and the presence of esophageal varices were recorded. PAG was measured by enzymatic methods. Cerebral magnetic resonance spectroscopy was performed in 10 cirrhotics. RESULTS: PAG was found to be higher in cirrhotics than control subjects 2.4+/-1.51 vs. 0.68+/-0.57IU/mg protein (P<0.001). PAG was also increased in patients with MHE and correlated with MELD, INR, esophageal varices and serum bile acids. A negative correlation was observed between PAG activity and intra-cerebral choline/creatine ratio (r=-0.67; P=0.035) and a positive correlation with glutamine plus glutamate/creatine ratio (r=0.78; P=0.007). In multivariate analysis using backward logistic regression, presence of MHE was the only variable independently related to altered enterocyte PAG. CONCLUSIONS: Enterocyte PAG is increased in cirrhotic patients and correlates with MHE. These data support a possible role for intestinal glutaminase in the pathogenesis of hepatic encephalopathy (HE) and could be a new target for future therapies.

Adult↗
PubMed2004

Tumour necrosis factor alpha polymorphisms are not involved in the development of steatosis in chronic hepatitis C.

AIM: To determine whether the different tumour necrosis factor alpha (TNF-alpha) promoter gene polymorphisms are involved in the development of steatosis in chronic hepatitis C. PATIENTS AND METHODS: One hundred and thirty patients (89 men and 41 women; mean age 42.5 +/- 12.3 years) with chronic hepatitis C were included. Insulin resistance was measured according to the Homeostasis model assessment (HOMA IR). Serum leptin levels were also obtained and the body mass index and fat mass were calculated. Liver biopsy was carried out in all the patients, and steatosis was measured as one of four stages (0 to 3): stage 0, no steatosis; stage 1, < 25% of hepatocytes with steatosis; stage 2, 25-50%; and stage 3, > 50%. DNA samples were obtained in order to describe the polymorphisms at the TNF-alpha promoter gene position. RESULTS: Fifty-nine of the 130 (45.38%) patients had different degrees of steatosis, while 71/130 (54.62%) were not steatosic. Six of the 59 (10.2%) patients with steatosis presented mutations at the -238 position of the TNF-alpha promoter region, while 5/71 (7.0%) patients without steatosis also showed mutations at this position (P=NS). Seventeen of the 59 (28.8%) steatosic patients showed a mutation at the -308 position, while 16/71 (22.5%) without steatosis also had this mutation (P=NS). Insulin resistance, beta cells reserve, insulin and leptin levels showed no differences between patients with or without mutations at the promoter region of the TNF-alpha gene. CONCLUSIONS: TNF-alpha mutations do not seem to play any role in the development of steatosis in chronic hepatitis C.

Adult↗
PubMed2004

Serum immunological profile in patients with chronic autoimmune cholestasis.

AIM: To compare patients who had biochemical and histological features of chronic autoimmune cholestasis (CAIC) using serological autoantibody profiling. METHODS: Patients (n = 174 CAIC; 79 AMA(-) and 95 AMA(+)) were profiled for the following antibodies: antinuclear antibodies (ANAs), antimitochondrial antibodies (AMAs), antismooth muscle actin (SMA, mainly F-actin), antiperinuclear cytoplasmic neutrophil antibodies (pANCAs), anti-SP100, anti-GP210, anti-M2 (2-oxo-acid dehydrogenase complexes), and antisoluble liver antigen (SLA). Liver specimens were reviewed according to staging, biliary interface activity, lobular hepatitis, granulomas, cholestasis, and florid ductal lesion. RESULTS: In patients who were AMA(-) by indirect immunofluorescence (IIF), 34.6% were positive for anti-M2 by immunoblotting. In 49 definitively AMA(-) patients, 24 (48.9%) showed ANA-primary biliary cirrhosis (PBC)-related antibodies (rim-like, multiple nuclear dots, anti-SP100, or anti-GP210). There were no differences in immunological, biochemical, or histopathological features between IIF-AMA(+) patients and AMA(-) patients with anti-M2 or ANA-PBC-related antibodies. AIH-related autoantibodies were found in 13 patients (7.5%). Patients with AMAs or ANA-PBC-related antibodies had higher IgM levels, whereas patients with antibodies highly specific for AIH had higher AST, bilirubin, and IgG levels, and AIH scores, and higher grades of lobular hepatitis. Overall, three distinct categories of patients were observed: AMA(+) or AMA(-) patients with ANA-PBC-related antibodies; AMA(-) patients with non-PBC-related ANAs; and patients with AIH-related antibodies together with serum PBC markers. CONCLUSION: Since these three groups had immunological, biochemical, and histopathological differences, they ought to be considered as separate clinical subentities rather than as merely AMA(-) or AMA(+) patients with autoimmune cholestasis.

Autoantibodies↗
PubMed2003

Serum leptin levels correlate with hepatic steatosis in chronic hepatitis C.

OBJECTIVES: Hepatic steatosis (HS) has been related to obesity and fibrosis in chronic hepatitis C (CHC). The aim of this study was to determine the role of leptin system in HS development. METHODS: Patients (n = 131) with biopsy-proven CHC, positive HCV RNA, and raised ALT were enrolled. Body mass index, percentage of body fat by skin fold measurement, and bioelectrical impedance analysis was calculated and serum leptin concentration measured. Intrahepatic HCV RNA, HS, necroinflammatory activity, and fibrosis were determined in liver biopsy tissue. RESULTS: HS was present in 63 patients (48.1%). Steatosis was evident in 32 of 91 patients (35.2%) infected with genotype 1 and in 22 of 27 patients (81.5%) with genotype 3a (p < 0.001). In patients infected by genotype 3a, HS correlated significantly with intrahepatic HCV RNA load (r = 0.78; p < 0.001). However, in genotype 1, HS was associated with host factors such as leptin, body mass index, percentage of body fat, and visceral obesity. Multivariate analysis showed genotype (OR = 11.54, 95% CI = 1.13-117.14, p = 0.038), leptin levels (OR = 1.09, 95% CI = 1.03-1.17, p = 0.008) and fibrosis (OR = 9.86, 95% CI = 2.11-5.86, p = 0.03) as independent variables of HS development. CONCLUSIONS: Hepatic steatosis was related to genotype, fibrosis degree, and serum leptin levels. Genotype 3 seems to have a viral specific steatogenic effect. Leptin seems to be a link between obesity and steatosis development in CHC genotype 1-infected patients.

Adult↗
PubMed2003

HLA class I B44 is associated with sustained response to interferon + ribavirin therapy in patients with chronic hepatitis C.

OBJECTIVE: The aim of this study was to assess the influence of host genetic factors on response to combination therapy for chronic hepatitis C infection. METHODS: Patients with biopsy-proved chronic hepatitis C infection were treated with interferon alone (n = 143) or combined therapy of interferon + ribavarin (n = 105; 46 treatment naïve, 59 relapsers). Human leukocyte antigen (HLA) class I was determined by microlymphocytotoxicity and class II by polymerase chain reaction-single specific oligonucleotide. The two biallelic tumor necrosis factor-alpha promoter polymorphisms were studied by a polymerase chain reaction-amplification refractory mutation system. Other variables measured were viral genotype, hepatitis C virus RNA load, liver function tests, and ferritin concentration. RESULTS: Univariate analysis indicated that patients bearing HLA B44+, DRB1*03, infected by genotype non-1, with higher concentrations of transaminases and shorter duration of infection showed a higher sustained response (SR) rate than those on combination therapy. HLA class II and TNF-alpha promoter polymorphisms were not related to SR. In multivariate analysis, non-1 genotype (OR 2.42, 95% CI 1.12-5.55, p = 0.026) and HLA B44+ (OR 4.84, 95% CI 1.3-17.8, p = 0.017) were the independent variables associated with SR. However, HLA B44+ was not associated with SR in patients treated with interferon alone. CONCLUSIONS: HLA class I B44 is related to a higher rate of SR in combination therapy but not in interferon monotherapy, whereas HLA class II, tumor necrosis factor-alpha -238A or -308A seem not to influence response to the antiviral therapy. These findings may be of value in therapy selection for hepatitis C-infected patients.

Adult↗