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Análisis mediante curvas ROC de los factores predictivos de respuesta al tratamiento con interferón más ribavirina en pacientes con hepatitis crónica C en recaída tras un tratamiento previo con interferón / ROC curve analysis of factors predictive of response to treatment with interferon plus ribavirin in patients with chronic hepatitis C relapse after previous interferon treatment

El objetivo de este estudio fue identificar, antes de iniciar el tratamiento y durante éste, variables predictivas de respuesta en pacientes con hepatitis crónica C en recaída tras un tratamiento previo con interferón a, retratados con IFN--a más ribavirina con un régimen estándar y un seguimiento de más de 40 meses. Se incluyeron 44 pacientes (40 con genotipo 1 y 4 con genotipo no 1), de los cuales cuatro (con genotipo 1) fueron excluidos por efectos adversos. La tasa de respuesta sostenida fue del 55 por ciento (50 por ciento genotipo 1, 100 por ciento no 1).El estadio de la lesión histológica (>2), la GPT (£26 UI/l) y la asociación de GPT y detección del RNA del VHC al primer y tercer mes de tratamiento fueron las variables con un área bajo la curva ROC e intervalo de confianza >0,5. La probabilidad de predecir la respuesta sostenida (valor predictivo negativo) si el estadio de la lesión histológica era 26 UI/l y la detección de RNA del VHC al primer mes, así como la detección al tercer mes, predicen con fiabilidad la falta de respuesta, pero con una baja sensibilidad (10 por ciento a 12 por ciento). Se concluye que es posible predecir con un grado de fiabilidad aceptable, no inequívocamente, la respuesta al tratamiento combinado. El 90 por ciento de estos pacientes son candidatos a mantener el tratamiento al menos durante 6 o 12 meses, mientras que aproximadamente un 10 por ciento serían subsidiarios de interrumpir el tratamiento precozmente por falta de respuesta (AU)

Retratamiento con interferón más ribavirina en pacientes con hepatitis crónica C, genotipo 1, no respondedores o con recaída tras un tratamiento previo con interferón. Seguimiento a largo plazo / Retreatment with interferon plus ribavirin in chronic hepatitis C patients with genotype 1 who had no response or a relapse with a previous interferon treatment

La finalidad de este estudio fue evaluar la tasa de respuesta sostenida, a los 6, 12 meses y al acabar el seguimiento (46,39 ñ 9,74 meses, extremos 6 y 60 meses), en pacientes con hepatitis crónica C retratados con interferón-a-2b (IFN-a) más ribavirina durante 6 meses (grupo A) o 12 meses (grupo B), en pacientes con recaída o no respondedores a la monoterapia previa con IFN-a, así como evaluar los cambios de la lesión histológica hepática. Se incluyeron 104 pacientes (100 con genotipo 1 y cuatro con genotipo no 1), 44 en recaída y 60 no respondedores, de los cuales el 20,2 por ciento se excluyeron por los efectos adversos. El 50 por ciento de los pacientes en recaída con genotipo 1 mostraron una respuesta sostenida, siendo mayor esta tasa (65 por ciento vs. 31,2; p <0.09) y menor la tasa de recidiva en el grupo B que en el A (7,2 por ciento vs. 61,5 por ciento; p <0.009), mientras que el 9,3 por ciento de los no respondedores mostraron una respuesta sostenida (A/B: 2/2). Los pacientes no respondedores con genotipo no 1 mostraron respuesta sostenida. La tasa de respuesta a los seis meses de seguimiento se mantiene constante excepto en los pacientes con recaída del grupo A (recidiva tardía 28,6 por ciento). La carga viral no se relacionó con la respuesta. El grado y el estadio de la lesión histológica mejoraron en los pacientes con respuesta sostenida (n=20; p <0.0001 y p <0.0001) y en un tercio de los no respondedores (n=45). El tratamiento combinado fue más eficaz con 12 que con 6 meses de tratamiento en los pacientes con recaída con genotipo 1, siendo baja la eficacia en los no respondedores. La evaluación de la respuesta a los 6 meses es fiable, excepto en los pacientes no respondedores con 6 meses de tratamiento. La lesión histológica mejoró sensiblemente con el tratamiento combinado, particularmente en los pacientes con respuesta sostenida. (AU)

[Retreatment with interferon plus ribavirin in chronic hepatitis C patients with genotype 1 who had no response or a relapse with a previous interferon treatment. Long term follow-up]. / Retratamiento con interferón más ribavirina en pacientes con hepatitis crónica C, genotipo 1, no respondedores o con recaída tras un tratamiento previo con interferón. Seguimiento a largo plazo.

The aims of this study were twofold: i) to evaluate the sustained response rate at 6 months, at 12 months and at the end of the follow-up [(46.39 +/- 9.74 months) (range: 6-60 months)] in patients with chronic hepatitis C retreated with interferon-a (IFN-a) plus ribavirin for 6 months (group A), 12 months (group B), in patients with relapse and those with no response to a previous course of monotherapy with IFN-a; and ii) to evaluate changes in the histological liver lesion. One hundred and four patients (100 with genotype 1 and four without), 44 with relapse and 60 non-responders, were included. A total of 20.2% of the patients were excluded because of side effects. Fifty percent of the relapsing patients with genotype 1 showed a sustained response. The sustained response rate was higher in group B than in group A, whereas the rate for the relapsing patients was lower in group B than in group A (13/20 vs. 5/16; 7.2% vs. 61.5%; p <0.09 and p <0.009, respectively). However, 9.3% of the non-responding patients showed a sustained response (A/B: 2/2). The relapsing patients who had a genotype other than 1 showed a sustained response. The sustained response rate was constant throughout the follow-up, except in relapsing patients from group A (the late relapse rate was 28.6%). The viral load was not related to the response. The grade and stage of the histological lesion improved in patients with sustained response (n=20) and in one-third of the non-responding patients (n=45) (p <0.0001 and p <0.0001). IFN in combination with ribavirin was more effective in relapsing patients with genotype 1 at 12 months than in those at 6 months of treatment, whereas the effectiveness in non-responding patients was low. The sustained response evaluation at 6 months was reliable, except in relapsing patients with 6 months of treatment. The histological lesion improved significantly with combination antiviral therapy.

[ROC curve analysis of factors predictive of response to treatment with interferon plus ribavirin in patients with chronic hepatitis C relapse after previous interferon treatment]. / Análisis mediante curvas ROC de los factores predictivos de respuesta al tratamiento con interferón más ribavirina en pacientes con hepatitis crónica C en recaída tras un tratamiento previo con interferón.

This study aimed to identify the factors predictive of response before the initiation of treatment and throughout the treatment period in patients with chronic hepatitis C relapse after treatment with interferon-a who were retreated with a standard regimen of interferon-a plus ribavirine and followed up for 40 months. Forty-four patients (40 with genotype 1, four without genotype 1) were included in the study. Four patients (genotype 1) were excluded because of adverse effects. The rate of maintained response was 55% (50% genotype 1, 100% non-genotype 1). The stage of histological damage (>2), glutamic-pyruvic transaminase (GPT) concentration (< or = 26 UI/l) and the association between the GPT concentration and the detection of the RNA-HCV in the first and third treatment months were the variables with an area under the ROC curve and a confidence interval >0.5. The probability of predicting a maintained response (negative predictive value) if the stage of histological lesion was <2 was 62.9%, while the positive predictive value was 100%. During the treatment, the disappearance of the RNA-HCV together with GPT values < or =26 in the first treatment month were the best predictive values. In this case, the negative predictive value was 78.3% and the positive predictive value was 76.5% (OR: 11.7, 2.6-52.2). Furthermore, the GPT value with the best predictive value (<26 UI/l) was a more effective predictor of the response to treatment than the normal value of the GPT. Finally, the GPT values >26 UI/l and the detection of RNA/HCV in the first or third treatment month were certain predictors of the absence of response but with low sensitivity (10-12%). It was concluded that is possible to predict the response to the combined treatment with an acceptable level of confidence, although not unequivocally. Ninety percent of the patients would be candidates for maintaining treatment for at least 6-12 months, while approximately 10% could undergo early interruption of treatment due to the absence of response.

Receiver operating characteristics curve analysis of factors predictive of nonresponse to interferon therapy in patients with chronic hepatitis C.

OBJECTIVES: 1) to identify pretreatment variables predictive of nonresponse to interferon-alpha (IFN-alpha) in patients with chronic hepatitis C, and 2) to establish a prognostic index in these groups using receiver operating characteristics curve analysis. METHODS: 132 patients were treated with IFN-alpha at a dose of 3 megaunits three times a week for 3-12 months. The response was compared in patients with a complete response vs nonresponders, and patients with a sustained response vs nonresponders plus relapsers. Factors predictive of response were identified by analyzing clinical, biochemical, virological and histological variables. RESULTS: The sustained response rate was 12.8% at 24 months of follow-up. The pretreatment characteristics with a predictive value (PV) according to area under the ROC curve and 95% confidence interval > 0.5 were age, known duration of infection, history of transfusion, GGT, serum ferritin levels, viral load, genotype, and grade and stage of the histological lesion. The positive PV (the probability of predicting absence of response when the variable is present) was notably greater than the negative PV (mean: 94.9% vs 24.8%, respectively). In addition, when 4 and 6 variables were present, the positive PV was 100% and sensitivity was 60.2% and 22.1%, respectively. The predictive variables independently associated with an absence of response were genotypes 1, 4 and 5, GGT > 24 IU/l and grade of the histological lesion > 6. CONCLUSIONS: It was possible to predict the absence of both primary and posttreatment response with an acceptable degree of reliability.

Análisis mediante las curvas ROC de los factores predictivos de no respuesta al tratamiento con interferón en pacientes con hepatitis crónica C / Receiver operating characteristics curve analysis of factors predictive of nonresponse to interferon therapy in patients with chronic hepatitis C

OBJETIVO: 1) identificar variables pretratamiento predictivas de no respuesta en 132 pacientes con hepatitis crónica C tratados con IFN-a con una dosis de 3 MU/3 vs/ 3-12 meses, comparando pacientes no respondedores más recaedores frente a pacientes respondedores sostenidos, y 2) establecer en este grupo un índice pronóstico mediante análisis con las curvas ROC. RESULTADOS: la tasa de respuesta sostenida fue del 12, 8 por ciento a los 24 meses de seguimiento. La edad, la duración conocida de la infección, el antecedente de transfusión, la GPT, la GGT, los niveles de ferritina sérica, la carga viral, el genotipo, el grado y el estadio de la lesión histológica fueron las características pretratamiento con valor predictivo (VP, área bajo la curva ROC e intervalo de confianza al 95 por ciento > 0,5). El valor predictivo positivo (la probabilidad de predecir la ausencia de respuesta cuando la variable está presente) es sensiblemente mayor que el VP negativo (media: 94,9 por ciento vs 24,8 por ciento). Por otro lado, la probabilidad de predecir la ausencia de respuesta cuando cuatro y seis variables estaban presentes fue del 100 por ciento y la sensibilidad fue del 60,2 y 22,1 por ciento, respectivamente. El genotipo 1, 4 y 5, los valores de GGT mayor a 24 Ul/l y el grado de lesión histológica mayor a seis fueron las variables con asociación pronóstica independiente con la ausencia de respuesta. CONCLUSIONES: es posible predecir con un grado de fiabilidad aceptable la ausencia de respuesta, tanto primaria como postratamiento (AU)

[ROC curve analysis of factors predictive of no response to interferon treatment in patients with chronic hepatitis C, genotype 1] / Análisis mediante curvas ROC de los factores predictivos de no respuestaal tratamiento con interferón en pacientescon hepatitis crónica C genotipo 1.

The objectives of this study included: 1) to identify pretreatment variables predictive of absence of response in 107 patients with chronic hepatitis C, genotype 1, treated with interferon-a (IFN-a) at a dose of 3 MU three times weekly for 3-12 months and classified into two groups: group A, nonresponders vs. patients with a complete response, and group B, nonresponding and relapsing patients vs. patients with a sustained response; and 2) to establish a prognostic index using ROC curve analysis. The rate of sustained response was 6.5% at the 24-month follow-up. The pretreatment characteristics with predictive value using ROC curves were as follows: in group A, age, GGT, serum ferritin, viral load, and grade and stage of the histological lesion; and in group B, known duration of infection, GPT, GGT, serum ferritin, viral load, and grade and stage of the histological lesion. In both group A and group B the positive predictive value (the probability of predicting an absence of response when the variable is present) was greater than the negative predictive value (mean: 84.3% vs. 41.1%, 99% vs. 16.5%, respectively). In group A, based on the prognostic index, the positive predictive value when three variables were present was 96% and the sensitivity was 63.5%, with the test being unequivocal in 6.5%, whereas when four or five variables were present, the positive predictive value was 97% and 100% and the sensitivity was 40.5% and 18%, respectively. In group B, the positive predictive value when two variables were present was 100% and the sensitivity was 87%, whereas when three, four, five and six variables were present the sensitivity was between 73% and 28%. In group A, age, GGT and ferritin were the predictive variables independently associated with an absence of response, with a relative risk of 6.5, 4.8 and 3.1, respectively, whereas in group B we did not find variables independently associated with an absence of response. It was concluded that in patients with genotype 1, it is possible to predict the absence of response to IFN therapy with a high degree of reliability.

[ROC curve analysis of factors predictive of non-response to interferon treatment in patients with chronic hepatitis C, genotype 1]. / Análisis mediante curvas ROC de los factores predictivos de no respuestaal tratamiento con interferón en pacientescon hepatitis crónica C genotipo 1.

The objectives of this study included: 1) to identify pretreatment variables predictive of absence of response in 107 patients with chronic hepatitis C, genotype 1, treated with interferon-a (IFN-a) at a dose of 3 MU three times weekly for 3-12 months and classified into two groups: group A, nonresponders vs. patients with a complete response, and group B, nonresponding and relapsing patients vs. patients with a sustained response; and 2) to establish a prognostic index using ROC curve analysis. The rate of sustained response was 6. 5% at the 24-month follow-up. The pretreatment characteristics with predictive value using ROC curves were as follows: in group A, age, GGT, serum ferritin, viral load, and grade and stage of the histological lesion; and in group B, known duration of infection, GPT, GGT, serum ferritin, viral load, and grade and stage of the histological lesion. In both group A and group B the positive predictive value (the probability of predicting an absence of response when the variable is present) was greater than the negative predictive value (mean: 84.3% vs. 41.1%, 99% vs. 16.5%, respectively). In group A, based on the prognostic index, the positive predictive value when three variables were present was 96% and the sensitivity was 63.5%, with the test being unequivocal in 6.5%, whereas when four or five variables were present, the positive predictive value was 97% and 100% and the sensitivity was 40.5% and 18%, respectively. In group B, the positive predictive value when two variables were present was 100% and the sensitivity was 87%, whereas when three, four, five and six variables were present the sensitivity was between 73% and 28%. In group A, age, GGT and ferritin were the predictive variables independently associated with an absence of response, with a relative risk of 6.5, 4.8 and 3.1, respectively, whereas in group B we did not find variables independently associated with an absence of response. It was concluded that in patients with genotype 1, it is possible to predict the absence of response to IFN therapy with a high degree of reliability.

[Comparative analysis of viral load by bDNA HCV RNA-2.0 and amplicor HCV monitor in patients with hepatitis C infection]. / Análisis comparativo de la carga viral mediante bDNA HCV RNA-2.0 y Amplicor HCV Monitor, en pacientes infectados por el virus de la hepatitis C.

BACKGROUND: Two standardized techniques, Quantiplex (bDNA-2.0) and Amplicor Monitor have been evaluated for the quantification of virus load of HCV with these objectives: a) determinate the relationship between virus load and genotype, and b) evaluate the virus load in serial serum samples and in patients with normal or slightly increased liver enzymes in an area with a high prevalence of genotype 1. RESULTS: A significant correlation of 0.7 (p < 0.0001) in virus load has been observed by both methods, but the virus load is smaller by Monitor than by Quantiplex and does not depend on genotype. The relationship Monitor/Quantiplex is smaller in patients with non-1 genotype than in patients with genotype 1a (p = 0.01) and 1b (p = 0.005). Virus characteristics are similar in patients with normal or slightly increased enzymes than in patients with high enzymes. Virus load by both methods is not related to the age, sex, know duration of the infection, transmission manner of the infection neither to the histologic activity index. CONCLUSION: The virus load not depends on genotype. The determination of virus load in a single serum sample adequately reflects the virus load are in several serum samples in patients with chronic HCV infection. The genotype and the virus load are similar in patients with normal enzymes than in patients with high enzymes.

Análisis mediante curvas ROC de los factores predictivos de no respuestaal tratamiento con interferón en pacientescon hepatitis crónica C genotipo 1 / ROC curve analysis of factors predictive of no response to interferon treatment in patients with chronic hepatitis C, genotype 1

Los objetivos del estudio fueron: 1) identificar variables pretratamiento predictivas de no respuesta en 107 pacientes con hepatitis crónica C con genotipo 1 tratados con IFN-a con una dosis de 3 MU tres veces por semana durante 3-12 meses distribuidos en dos grupos: grupo A, no respondedores frente a pacientes con respuesta completa, y grupo B, no respondedores más recaedores frente a los pacientes con respuesta sostenida; y 2) establecer un índice pronóstico mediante análisis de las curvas ROC. La tasa de respuesta sostenida fue del 6,5 por ciento a los 24 meses de seguimiento. En el grupo A, la edad, la GGT, la ferritina sérica, la carga viral, el grado y el estadio de la lesión histológica, y en el grupo B la duración conocida de la infección, la GPT, la GGT, la ferritina sérica, la carga viral, el grado y el estadio de la lesión histológica, fueron las características pretratamiento con valor predictivo según las curvas ROC. El valor predictivo positivo (probabilidad de predecir la ausencia de respuesta cuando la variable está presente) fue mayor que el valor predictivo negativo (media 84,3 por ciento vs. 41,1 por ciento, 99 por ciento vs. 16,5 por ciento, respectivamente) en ambos grupos. En el grupo A, según el índice pronóstico, el valor predictivo positivo cuando estaban presentes tres variables fue del 96 por ciento y la sensibilidad del 63,5 por ciento, siendo la prueba inequívoca en un 6,5 por ciento, mientras que cuando estaban presentes cuatro o cinco variables el valor predictivo positivo fue del 97 por ciento y el 100 por ciento, y la sensibilidad del 40,5 por ciento y 18 por ciento. En el grupo B, el valor predictivo positivo cuando estaban presentes dos variables fue del 100 por ciento y la sensibilidad del 87 por ciento, mientras que cuando estaban presentes tres, cuatro, cinco o seis variables la sensibilidad fue del 73 por ciento al 28 por ciento. En el grupo A, la edad, la GGT y la ferritina fueron las variables con asociación pronóstica independiente con la ausencia de respuesta, con un riesgo relativo de 6,5, 4,8 y 3,1, respectivamente, mientras que en el grupo B no encontramos variables asociadas independientemente con la ausencia de respuesta. Se concluye que en los pacientes con genotipo 1 es posible predecir, con una elevada fiabilidad, la ausencia de respuesta al tratamiento con IFN (AU)

Comparative analysis of quantification of viral load in patients infected with hepatitis C virus: quantiplex HCV RNA assay and amplicor monitor assay.

OBJECTIVE: two standardized techniques, Quantiplex HCV RNA 2.0 (bDNA) and Amplicor Monitor, were evaluated for the quantification of hepatitis C virus (HCV) load. Our objectives were: 1) to determine the relationship between viral load and genotype, and 2) to evaluate viral load in serial serum samples and in patients with normal or slightly elevated liver enzyme values in an area with a high prevalence of genotype 1. RESULTS: the viral loads detected with the two methods correlated significantly (r = 0.7, p < 0.0001), but viral load was smaller with the Monitor than with the Quantiplex assay, and was independent of genotype. The Monitor/Quantiplex ratio was lower in patients with a non-1 genotype than in patients with genotype 1b. Virological characteristics were similar in patients with normal or slightly elevated enzyme levels and in patients with elevated enzyme values. Neither method showed a relationship between viral load and age, sex, duration of the infection, mode of transmission, or histological activity index. CONCLUSION: viral load was not dependent on genotype. Measurement of viral load in a single serum sample adequately reflected the viral load measured in several serum samples from patients with chronic HCV infection. Patients with normal liver enzyme levels are not good candidates, in virological terms, for treatment with interferon.

[The effect of iron depletion on the response to interferon treatment in patients with chronic hepatitis C. Pilot study]. / Efecto de la depleción de hierro sobre la respuesta al tratamiento con interferón en pacientes con hepatitis crónica C. Estudio piloto.

UNLABELLED: It has been reported that increase in serum ferritin levels and/or in hepatic iron content is associated with a poor response to interferon treatment in patients with chronic hepatitis C (CH-C). AIM: To determinate whether iron depletion by phlebotomy (PB) increases the response to interferon therapy in chronic hepatitis C. PATIENTS AND METHODS: We have evaluated 12 patients with CH-C (genotype 1b = 11, 1a = 1), increased ALT levels, positive serum VHC-RNA and increased serum ferritin levels (> 220 ng/ml), including 8 previously non responders to interferon therapy and 4 naive subjects. Phlebotomies were performed weekly (mean number per patient: 6, range: 5-12) until serum ferritin levels were < 100 ng/ml, followed by interferon treatment (3MU thrice weekly for 3-12 months depending on the response). RESULTS: Multiple regression analysis showed that serum ferritin levels were not related to serum ALT levels (p = 0.18) or viral load (p = 0.06). Serum ALT levels decreased significantly post-PB (58 U/l, range: 35-141 U/l) as compared to pretreatment levels (164 U/l, range: 51-216 U/l, p < 0.006) and normalized in two subjects. HCV-RNA was positive in one of the latter and negative in the other. Eleven of the twelve patients did not respond to interferon after three months of therapy (increased serum ALT levels in 10 subjects and positive HCV RNA in 11). One additional patient, who had not been treated previously with interferon and had low pretreatment viral load, had a sustained response after 12 months of interferon therapy. Viral load did not decreased either with PB or following interferon treatment. By contrast, serum ferritin levels did not increase with interferon treatment or during the 6 month follow-up period. CONCLUSIONS: Decreasing serum ferritin levels by phlebotomies does not increase HCV erradication rate after interferon treatment. Sustained response to interferon therapy is an infrequent event and is more dependent on viral factors (viral load and genotype).

Response to treatment with interferon-alfa in patients with chronic hepatitis C and high titers of -M2, -M4 and -M8 antimitochondrial antibodies.

UNLABELLED: The prevalence of antimitochondrial antibodies (AMA) in chronic hepatitis C is 2%; titers of AMA are usually low (< 1:40). The prevalence decreases to 0.5% when the results are verified by determination of the M2 subtype (anti-M2, ELISA). In patients in whom both hepatitis C virus (HCV) and AMA are present, the therapeutic decision to give interferon-alfa is complicated, because AMA may be 'real', and if it reflects primary biliary cirrhosis, cholestasis can be triggered or exacerbated. This does not occur when AMA positivity results from induction by hepatotropic C virus; however, this is rarely the case when AMA titers are high (> 1:160). OBJECTIVE: to undertake a preliminary analysis of the submitochondrial profile of AMA in three patients with chronic hepatitis C and positive AMA titers (> 1:160). METHODS: we determined antibodies to submitochondrial particles (subtypes) -M2, -M4 and -M8 by ELISA, complement binding (CB) and western immunoblotting with Immunoblot-M2 or WIB-M2 (immunoreactive bands). RESULTS: two patients were positive for mitochondrial subtypes by ELISA (IgG/IgM subclass) and CB (ELISA M2 470/365 in patient 1 and 600/1370 in patient 2; M4 490/1200 in patient 2. CB M2 1:128, M4 1:64, M8 1:64 in patient 1, M2 1:128 in patient 2). Immunoreactive epitopes (bands) were detected with WIB-M2 for 70, 56, 51, 45 and 36-kDa molecules. Interferon-alfa treatment was unsuccessful, with biochemical exacerbation of cholestasis. In contrast, the patient with no submitochondrial particles according to ELISA, CB and WIB-M2 results responded favorable to this drug. CONCLUSION: these preliminary results suggest that analyses to detect antibodies to submitochondrial particles (-M2, -M4 and -M8 subtypes) and -M2-immunoreactive epitopes in patients with chronic hepatitis C and AMA titers > 1:160 facilitates the diagnosis of primary biliary cirrhosis, and establishes a contraindication for treatment with interferon-alfa despite the presence of HCV infection.

[Carcinoid syndrome: advances in diagnosis and treatment]. / Síndrome carcinoide: avances en diagnóstico y tratamiento.

Carcinoid is the most common endocrine digestive tumor. The carcinoid syndrome resulting from the variety of amines and peptides produced by this tumor is usually apparent once there are metastases to the liver. Tumors with direct systemic venous drainage seldom produce a carcinoid syndrome without the presence of liver metastasis. This may occur because the hormone escapes the normal metabolic pathway (monoamine oxidase) in the liver. The most significant and important advance in diagnosis for tumor localization has been the introduction of scintigraphy using 111In-labeled octreotide. Current management of carcinoid syndrome should consider the spontaneous course of the disease and the severity of clinical symptoms, and includes different therapeutic options as hepatic resection, chemoembolization, medical treatment with the long-acting analogues of somatostatin and liver transplantation.

[Early prediction of lack of response to treatment with interferon and interferon plus ribavirin using biochemical and virological criteria in patients with chronic hepatitis C]. / Predicción precoz de no respuesta durante el tratamiento con interferón e interferón más ribavirina, mediante criterios bioquímicos y virológicos, en pacientes con hepatitis crónica C.

The objectives of this study were the following: 1) to evaluate the predictive value of the detection of RNA-HVC compared to GPT in the third month of treatment in patients with chronic hepatitis C treated with IFN, and at the first and third month in patients treated with IFN and ribavirin for 6 and 12 months. The study included: A) 80/132 patients treated with IFN (3 MU/3 times a week for 6-12 months), and B) 70/110 patients who had previously not responded to IFN, and who were treated with combination therapy (IFN: standard dose, ribavirin: 1200 mg/day) for 6 months (n = 40) and 12 months (n = 30). In group A, the positive predictive value (the probability of predicting the lack of response if the RNA-HVC was positive or if the GPT was elevated at the third month) was greater for RNA-HVC than for GPT (97.9% vs. 94.4%), although the response was not unequivocal (2.3% vs. 10.5%). The negative predictive value was 48.6% vs. 36.2%, respectively. The prediction level (odds ratio) of RNA-HVC and of GPT was 39.7 vs. 8.78 (p <0.000001 vs. p <0.002). The positive predictive value was 97.6% in patients with genotype 1, 4 and 5, and 100% in those with genotype 2 and 3. In group B, the positive predictive value was also greater for RNA-HVC than for GPT at the first month (100% vs. 94.4%) following six months of therapy, the odds ratio being infinite vs. 7.6. The positive predictive value was greater for RNA-HVC at the third month than at the first (100% vs. 91%), whereas it was similar for GPT (100%) with 12 months of therapy, the odds ratio being greater for GPT than for RNA-HVC at the first month (infinite and 7.27). The following was concluded: 1) detection of RNA-HVC at the third month of treatment with IFN predicts in advance a lack of response in patients, with a minimum risk of error; 2) in patients with six months of combined therapy, the detection of RNA-HVC at the first month is extremely reliable in the prediction of a lack of response, whereas after 12 months of combined therapy, elevated GPT values at the first month and the detection of RNA-HVC at the third are highly predictive of a lack of response.

High incidence of allograft cirrhosis in hepatitis C virus genotype 1b infection following transplantation: relationship with rejection episodes.

The natural history of hepatitis C virus (HCV) infection following liver transplantation and predictors of disease severity remain controversial. The aims of the study were to assess in a homogeneous population of 81 cyclosporine-based HCV-infected liver transplant recipients mostly infected with genotype 1b and undergoing strict protocol annual biopsies: 1) the histological progression of posttransplantation HCV disease and, in particular, the incidence of HCV-related graft cirrhosis within the first 5 years after surgery; and 2) the relationship between progression to cirrhosis and i) rejection episodes and ii) first-year liver biopsy findings. We studied 81 consecutive HCV-RNA-positive patients (96% genotype 1b) undergoing liver transplantation between 1991 and 1996 with a minimum histological follow-up of 1 year. All patients received cyclosporine-based immunosuppression and underwent protocol yearly liver biopsies for the first 5 years. The mean histological follow-up was 32 months (range, 12-60 months). Biopsies were scored according to the histological activity index (HAI), with separate evaluation of grade (activity) and stage (fibrosis). Histological hepatitis, present in 97% of patients in the most recent biopsy, was moderate or severe in 64%. Twelve patients developed HCV-related cirrhosis at a median time of 24 months (range, 12-48 months), with an actuarial rate of HCV-cirrhosis of 3.7%, 8.5%, 16%, 28%, and 28% at 1, 2, 3, 4, and 5 years, respectively. Rejection was significantly more common among patients with cirrhosis versus those without (83% vs. 48%; P =.02), with an association between the incidence of cirrhosis and the number of rejection episodes: 5%, 15%, and 50% in patients without rejection, one and two episodes, respectively (P =.001). The degree of activity and fibrosis score in the first-year biopsy were higher in patients who developed cirrhosis than in those who did not (P =.008 and.18, respectively). In conclusion, HCV genotype 1b-infected liver recipients are at a high risk of developing graft cirrhosis in the first 4 to 5 years following transplantation, especially those with previous rejection episodes. First-year liver biopsies may help to sooner identify patients at the highest risk, improving further patient management.

Early development of chronic active hepatitis in recurrent hepatitis C virus infection after liver transplantation: association with treatment of rejection.

BACKGROUND/AIMS: We retrospectively studied 63 consecutive patients (mean age 54+/-8) with hepatitis C virus genotype 1b recurrence after liver transplantation and with a minimum histological follow-up of 1 year, in order to determine whether an early severe recurrence, defined as the development of chronic active hepatitis within the first 2 years post-liver transplantation, was associated with increased immunosuppression. METHODS: The 1st year immunosuppression data (rejection episodes, boluses of methyl-prednisolone, cumulative doses of prednisone and azathioprine, OKT3 use) were recorded, and evaluated as predictive of severe recurrence at 1 and 2 years post-liver transplantation. Chronic active hepatitis and rejection were defined by histological criteria. Immunosuppression consisted of cyclosporine, azathioprine and prednisone. The treatment of rejection was based on a "bolus" of 1 g methyl-prednisolone/3 days. RESULTS: At 1 year, 64% (40/63) of the patients had chronic active hepatitis, whereas of the 40 patients who had a 2nd year biopsy available, 75% had chronic active hepatitis at 2 years. At 1 year post-liver transplantation, no significant association was observed between immunosuppression and the development of chronic active hepatitis. In contrast, at 2 years, rejection (p=0.006), treatment of rejection (p=0.05), methyl-prednisolone boluses (p=0.013) and the number of rejection episodes (p=0.0034) occurring during the 1st year post-liver transplantation were significantly more common in patients with chronic active hepatitis. There was also a trend towards higher cumulative steroids (9447+/-3176.5 vs 7891.5+/-2111 mg) and higher cumulative azathioprine doses (13472+/-11154 vs 6233.5+/-5937 mg) in patients with chronic active hepatitis as compared to those who did not develop chronic active hepatitis. CONCLUSIONS: Rejection and/or its treatment may accelerate the natural history of hepatitis C virus genotype 1b infection post-liver transplantation.