[Comparative study of two models that use biochemical parameters for the non-invasive diagnosis of fibrosis in patients with hepatitis C]. / Estudio comparativo de dos modelos que utilizan parámetros bioquímicos en el diagnóstico no invasivo de la fibrosis hepática en pacientes con hepatitis C.

BACKGROUND AND OBJECTIVE: Several models for the prediction of liver fibrosis have been developed which consist of the measurement of routine laboratory data: a) a model combining platelets, gamma-glutamil-transpeptidase, cholesterol and age (Forns model), and b) a model using an aspartate-aminotransferase to platelet ratio index (APRI). Our study was aimed to compare both non-invasive methods to predict mild fibrosis (F0-F1) or to confirm advanced fibrosis (F3, F4) in patients with chronic hepatitis C. PATIENTS AND METHOD: We included 199 patients with chronic hepatitis. The average age (standard deviation) was 41 (11) years (16-66), and there were 117 men and 82 women. We found a genotype 1 in 108 patients (54.2%), 45 had a non-1 genotype (22.6%), and 46 (23.1%) had an unknown genotype. Mild fibrosis stage (F0-F1) was found in 96 patients, F2 in 52 and advanced fibrosis (F3-F4) in 51 patients. We calculated the APRI and the Forns's index. RESULTS: Patients infected with genotype 1 were older (44 [11] vs 36 [4.3] years; p = 0.001), presented higher levels of cholesterol (179 [40] vs 160 [42] mg/dl; p = 0.05) and lower levels of alanine-aminotransferase (112 [86] vs 169 [87] IU/l; p = 0.03). The Forns's model predicted mild fibrosis (F0-F1) in 71.4% while the APRI model did it in 72.7%. The Forns's model confirmed advanced fibrosis in 78.6% against 54.2% from the APRI one. The predictive capacity in both models increased when analyzing patients with the genotype 1. Moreover, the predictive capacity of advanced fibrosis or exclusion of significant fibrosis reached more than 90% when both models were used together in patients with a genotype 1. CONCLUSIONS: Non-invasive methods for the prediction of liver fibrosis can be very useful in clinical practice, mainly in patients with genotype 1 when the two methods are used together.

Estudio comparativo de dos modelos que utilizan parámetros bioquímicos en el diagnóstico no invasivo de la fibrosis hepática en pacientes con hepatitis C / Comparative study of two models that use biochemical parameters for the non-invasive diagnosis of fibrosis in patients with hepatitis C

FUNDAMENTO Y OBJETIVO: Recientemente se han desarrollado 2 modelos de cálculo de fibrosis utilizando parámetros bioquímicos analizados en la práctica habitual: a) las plaquetas, la gammaglutamiltranspeptidasa, el colesterol y la edad (índice Forns) y b) el cociente aspartato ahh aminotransferasa/plaquetas (APRI). El objetivo de nuestro estudio ha sido comparar la utilidad de ambos métodos no invasivos para detectar fibrosis leve (F0-F1) o fibrosis avanzada (F3-F4) en pacientes con hepatitis C crónica. PACIENTES Y MÉTODO: Incluimos a 199 pacientes (117 varones y 82 mujeres) con hepatitis crónica C, con una edad media (desviación estándar) de 41 (11) años (extremos, 16-66). Un totalde 108 pacientes (54,2%) eran de genotipo 1, 45 de genotipo no 1 (22,6%), y en 46 (23,1%)se desconocía el genotipo. La distribución de los pacientes según el estadio de fibrosis fue:leve (F0-F1) en 96 pacientes, F2 en 52 y avanzado (F3-F4) en 51. Calculamos el resultado delíndice APRI y del índice de Forns. RESULTADOS: Los pacientes infectados por el genotipo 1 eran mayores (media de 44 [11] frente a 36 [4,3] años; p = 0,001), presentaban valores más altos de colesterol (media de 179 [40]frente a 160 [42] mg/dl; p = 0,05) e inferiores de alaninaminotransferasa (media de 112 [86]frente a 169 [87] UI/l; p = 0,03). El modelo de Forns predijo fibrosis leve (F0-F1) en el 71,4%mientras que el modelo APRI lo consigue en un 72,7%. El modelo de Forns predice fibrosis avanzada en el 78,6% frente al 54,2% del modelo APRI. La capacidad predictiva de ambos modelos aumentó al analizar de forma separada el grupo de pacientes con hepatitis C de genotipo1, sobre todo cuando se utilizaron de forma conjunta, demostrando una capacidad de predecir fibrosis leve (F0-F1) del 95,2% y de detectar fibrosis avanzada del 91,7%.CONCLUSIONES: Los métodos bioquímicos no invasivos para la predicción de la fibrosis pueden ser muy útiles en la práctica clínica, sobre todo en el grupo de pacientes con hepatitis C genotipo1, cuando se utilizan ambos modelos de forma conjunta

BACKGROUND AND OBJECTIVE: Several models for the prediction of liver fibrosis have been developed which consist of the measurement of routine laboratory data: a) a model combining platelets,gamma-glutamil-transpeptidase, cholesterol and age (Forns model), and b) a model using an aspartate-aminotransferase to platelet ratio index (APRI). Our study was aimed to compareboth non- invasive methods to predict mild fibrosis (F0-F1) or to confirm advanced fibrosis (F3,F4) in patients with chronic hepatitis C.PATIENTS AND METHOD: We included 199 patients with chronic hepatitis. The average age (standard deviation) was 41 (11) years (16-66), and there were 117 men and 82 women. We founda genotype 1 in 108 patients (54.2%), 45 had a non-1 genotype (22.6%), and 46 (23.1%)had an unknown genotype. Mild fibrosis stage (F0-F1) was found in 96 patients, F2 in 52 and advanced fibrosis (F3-F4) in 51 patients. We calculated the APRI and the Forns’s index. RESULTS: Patients infected with genotype 1 were older (44 [11] vs 36 [4.3] years; p = 0.001),presented higher levels of cholesterol (179 [40] vs 160 [42] mg/dl; p = 0.05) and lower levels of alanine-aminotransferase (112 [86] vs 169 [87] IU/l; p = 0.03). The Forns’s model predicted mild fibrosis (F0-F1) in 71.4% while the APRI model did it in 72.7%. The Forns’s model confirmed advanced fibrosis in 78.6% against 54.2% from the APRI one. The predictive capacity in both models increased when analyzing patients with the genotype 1. Moreover, the predictive capacity of advanced fibrosis or exclusion of significant fibrosis reached more than 90%when both models were used together in patients with a genotype 1.CONCLUSIONS: Non-invasive methods for the prediction of liver fibrosis can be very useful in clinical practice, mainly in patients with genotype 1 when the two methods are used together

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.

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.

HLA class II genotype influences the type of liver injury in drug-induced idiosyncratic liver disease.

Drug-induced idiosyncratic liver disease (DIILD) depends largely on host susceptibility factors. Small studies support the genetic influence of human leukocyte antigen (HLA) class II molecules on the predisposition to DIILD. We sought associations between HLA-DRB and -DQB alleles and DIILD considered collectively or according to the biochemical expression of liver damage. We studied a total of 140 patients with a definitive or probable diagnosis of DIILD, as assessed with the Council for International Organizations of Medical Sciences scale, with 635 volunteer bone marrow and blood donors serving as controls. HLA-DRB1* and -DQB1* genotyping was performed by hybridization with sequence-specific oligonucleotides after genomic amplification. The group with DIILD did not differ from control subjects with regard to the distribution of HLA-DRB and -DQB antigens. The frequencies of alleles DRB1*15 (35.4% vs. 18.6% of controls; P =.002; odds ratio [OR] 2.31) and DQB1*06 (61.5% vs. 40.8%; P =.001; OR 2.32) were significantly increased in patients with the cholestatic/mixed type of liver damage in comparison to healthy subjects. By contrast, frequencies of alleles DRB1*07 (16.9% vs. 35.4%; P =.003; OR 0.37) and DQB1*02 (32.3% vs. 55.8%; P =.0003; OR 0.39) were significantly decreased. In conclusion, there is no association between any specific HLA allele and the propensity to develop DIILD. However, the genetic influence associated with HLA class II alleles appears to play a role in the biochemical expression of liver injury in cholestatic/mixed hepatotoxicity and may explain why a given drug may cause different patterns of liver damage.