Mycophenolate mofetil-induced neutropenia in liver transplantation.

BACKGROUND: Mycophenolate mofetil (MMF) is a potent, safe immunosuppressive agent for rescue therapy of acute and chronic rejection in orthotopic liver transplant recipients. It helps to reduce the serious toxic side effects of calcineurin inhibitors (CNIs). The side effects of MMF, such as bone marrow toxicity, have been reported. Herein we report four patients who underwent liver transplantation and developed neutropenia while receiving MMF. METHODS: Between April 2002 and October 2003, we performed 24 liver transplants in 25 patients. Eighteen patients were given MMF for the following reasons: renal failure in nine (50%); treatment of acute rejection in three (16.6%); primary prophylaxis of rejection in five (27.7%); and CNI withdrawal in one (5.5%). RESULTS: Of the 18 patients treated with MMF, there were 11 men (61.1%) and seven women (38.8%), with an overall mean age of 55.5 years. This therapy was ceased in four patients due to neutropenia (22%). Discontinuation of MMF was followed by a rapid and spontaneous rise in neutrophils in two patients. Granulocyte colony stimulating factor (GCSF) was administered to one patient and in another a bone marrow biopsy was performed due to persistent anemia, leukopenia, and thrombocytopenia. The mean time from starting MMF to the development of neutropenia was 4 months. Only the third patient showed elevated levels of MMF. CONCLUSIONS: MMF is a potent immunosuppressive agent in liver transplantation. However, because serious hematologic toxicity has been reported, we recommend caution in administration and careful monitoring of blood levels.

Flutamide-induced hepatotoxicity: report of a case series.

OBJECTIVE: To evaluate the characteristics of flutamide induced hepatotoxicity. MATERIAL AND METHODS: In this retrospective study we have analyzed all cases of flutamide hepatotoxicity submitted to the Andalucian Registry of drug-induced liver disease. Data were collected using a structured reporting form. Causality assessment was performed using two clinical scales: the standard CIOMS scale and the recently developed María and Victorino scale. RESULTS: Nine of 185 patients (4.9%) were identified. In 8 male patients, mean age 75 years (range 65-83), flutamide was indicated for palliative therapy of disseminated prostatic carcinoma, and in one young female (14 years) was given for the treatment of facial hirsutism. The mean duration of the flutamide therapy was 151 days (range 4-443). All patients presented with overt liver injury, the most frequent features being asthenia, anorexia, weight loss, nausea, vomiting and jaundice. No patient showed hypersensitivity features. In two patients (22%) the hepatic damage evolved to fulminant liver failure, one of them undergoing a liver transplantation and the other subsequently died. An additional patient died of a non-hepatic related cause when his liver function was improving. Causality assessment by the two clinical scales did not exclude any case, but the two patients who died where classified as unlikely by the María and Victorino scale. CONCLUSIONS: Flutamide can induce severe acute hepatitis, probably due to an idiosyncratic metabolic mechanism. Liver tests monitoring should probably be mandatory during the first months of flutamide therapy and the drug withdrawn if transaminases began to increase.

Hepatotoxicidad por flutamida: análisis de una serie / Flutamide-induced hepatotoxicity: report of a case series

Objetivo: evaluar las características de la hepatotoxicidad por flutamida.Material y métodos: análisis de 9 casos de toxicidad hepática secundaria a este fármaco remitidos al Registro Andaluz de Hepatopatías asociadas a medicamentos. La información se recogió en un protocolo estructurado. La imputabilidad de la flutamida se estimó en cada uno de los casos por dos escalas diagnósticas; Council for International Organization of Medical Sciences (CIOMS) y una recientemente validada (María y Victorino).Resultados: 9 de 185 casos (4,9 por ciento) de hepatotoxicidad remitidos al registro eran debidos a flutamida. En 8 pacientes varones con edad media de 75 años (rango 65-83), la flutamida se indicó para la paliación del carcinoma de próstata metastásico, y en una mujer de 14 años para el tratamiento del hirsutismo facial. El tiempo medio de duración del tratamiento fue de 151 días (rango 4-433). El episodio de hepatotoxicidad tuvo expresión clínica en todos los pacientes, siendo las manifestaciones más frecuentes: astenia, anorexia, pérdida de peso, náuseas, vómitos e ictericia. Ningún paciente presentó manifestaciones de hipersensibilidad. Dos pacientes (22 por ciento) presentaron fallo hepático fulminante, falleciendo uno y realizándose transplante hepático en el otro. Un tercer paciente falleció cuando la lesión hepática estaba en fase de resolución. No hubo ningún caso excluido en la evaluación de im putabilidad, pero los dos casos de éxitus fueron clasificados como dudosos por la escala de María y Victorino. Conclusiones: flutamida puede producir hepatitis aguda grave, ocasionalmente fulminante, por un mecanismo presuntamente de idiosincrasia metabólica. Debería monitorizarse el perfil hepático durante los primeros meses de tratamiento con flutamida, suspendiéndose el fármaco en caso de detectarse alteraciones (AU)

Historia natural de la infecciónpor virus C de la hepatitis

No disponible

Estudio multicéntrico retrospectivo de la respuesta al interferón en la hepatitis crónica por VHB / Multicenter retrospective study of response to interferon in choric hepatitis B

OBJETIVO: el fármaco más ampliamente utilizado en el tratamiento de la hepatitis crónica B ha sido el interferón alfa, con unas tasas de respuesta del 25-40 por ciento. Los objetivos a corto plazo del tratamiento son inducir la eliminación de los marcadores de replicación viral en suero, reducir los niveles de transaminasas y mejorar la histología hepática. Son factores predictores de respuesta unos niveles elevados de transaminasas, una concentración baja de DNA-VH13 y signos de actividad histológica fundamentalmente. Los objetivos de este estudio han sido conocer de forma retrospectiva la respuesta al INF-a en pacientes con hepatopatía crónica por VHB, de forma global y según el HBeAg, así como analizar los factores predictores de respuesta al mismo. PACIENTES Y MÉTODOS: hemos realizado un estudio multicéntrico retrospectivo de la respuesta al interferón alfa en 132 pacientes con hepatopatía crónica por el virus B, tanto de forma global como teniendo en cuenta el HBeAg y analizado los factores predictores de respuesta al mismo. RESULTADOS: globalmente, 59 pacientes (45 por ciento) tuvieron respuesta completa mantenida al INF, 61 (46 por ciento) no respondieron y 12 (9 por ciento) recidivaron. Ninguno negativizó el HBsAg. En los pacientes HBeAg+, 30 pacientes respondieron de forma mantenida (46 por ciento), 22 no respondieron (49 por ciento) y tres (5 por ciento) recidivaron, siendo similar en los casos HBeAg- (43, 43 y 14 por ciento, respectivamente). De todos los parámetros estudiados sólo las transaminasas sirvieron para predecir la respuesta global, observando en los pacientes con respuesta completa mantenida unas cifras significativamente más altas que en los no respondedores. En los HBeAg+ sólo la edad fue predictora de respuesta y en los HBeAg- la histología. El sexo, el antecedente epidemiológico, tipo de IFN, dosis, tiempo de tratamiento y tipo de virus no tuvieron influencia en la respuesta. CONCLUSIONES: hemos observado una respuesta mantenida global al IFN del 45 por ciento con una tasa de seroconversión (AU)

Multicenter retrospective study of response to interferon in chronic hepatitis B.

AIM: The only agent known to have a lasting beneficial effect in chronic hepatitis B is interferon alpha, which achieves long-term remission in 25-40% of the patients. The goals of treatment are to induce clearance of HBV DNA from serum, to return serum aminotransferases to normal, and to improve histological findings in the liver. The most important factors predictive of response to treatment are high serum aminotranferases levels, low serum HBV DNA concentrations, and active histologic changes on liver biopsy. The aim of this study was to assess the response to interferon alpha in patients with chronic hepatitis B and to analyze the factors predictive of response. METHODS: We conducted a multicenter retrospective study to investigate the effect of interferon treatment in 132 patients with chronic hepatitis B in overall terms and based on HBeAg, and factors predictive of response. RESULTS: A overall sustained response was noted in 59 of 132 interferon-treated patients (45%) and 61 patients were nonresponders (46%). 12 patients relapsed (9%). None of the patients had negative HBsAg. No difference was observed in the response rate between the two treatment groups (HBeAg-positive and HBeAg-negative patients). Overall, high initial levels of serum AST and ALT predicted a good response. Age and liver biopsy findings were factors predictive of response in HBeAg-positive and HBeAg-negative patients respectively. Sex, epidemiological factors, treatment and type of virus did not correlate with the response to interferon. CONCLUSIONS: A sustained response to interferon alpha was observed in 45% of the patients with chronic hepatitis B. HBeAg seroconversion was found in up to 50% of HBeAg-positive patients. None of the patients had negative HBsAg. Overall, the response rate was higher in patients with high pretreatment serum aminotransferase levels. Age was the predictive factor in HBeAg-positive patients, and histological features were predictive in the HBeAg-negative group. However, further studies in a larger patient population are necessary to obtain well-substantiated conclusions.

Acute liver injury associated with the use of ebrotidine, a new H2-receptor antagonist.

BACKGROUND/AIM: Ebrotidine is a new H2-receptor antagonist marketed in Spain in early 1997 and withdrawn in July 1998. We report 11 cases of acute liver injury related to ebrotidine and submitted to a Regional Registry of Hepatotoxicity between June 1997 and August 1998. METHODS: In all cases a structured protocol was used to ascertain the role of ebrotidine and to exclude other causes (viral, immunologic, metabolic) of liver injury. RESULTS: All patients showed clinical symptoms of acute hepatitis, with a marked increase in aminotransferase activities (ALT values ranging from 15 to 91 times the upper limit of normal). Total bilirubin values were also greatly increased (mean 16 mg/dl), and the liver injury was defined as hepatocellular. Features of hypersensitivity were absent. Liver biopsy was done in three patients. Histopathological examination revealed mainly centrozonal necrosis (two cases) or massive necrosis (one patient). Withdrawal of the drug was followed by a gradual improvement in liver dysfunction, except in one patient who developed fulminant hepatic failure and died. There was a positive response to rechallenge in one patient after an inadvertent drug administration. CONCLUSION: Ebrotidine therapy seems to be associated with severe acute liver injury, and therefore its benefit/risk ratio is unfavorable. The relative rareness and unpredictability of the injury, the lack of dose-relationship and the absence of hallmarks of drug allergy are suggestive of an idiosyncratic metabolic mechanism.

Response of chronic hepatitis C to interferon-alpha treatment and relationship with iron metabolism.

AIM: to prospectively analyze the influence of iron metabolism of the response to interferon-alpha therapy in chronic hepatitis C. METHODS: ninety-two patients with chronic hepatitis C treated with recombinant alpha-interferon were included. Basal serum levels of iron, ferritin and transferrin saturation were compared in responding and nonresponding patients. Additional epidemiologic, histologic and biochemical variables were studied as predictors of response to interferon-alpha therapy. RESULTS: we studied 57 men (62%) and 35 women (35%) with a mean age of 40 years. Biopsy specimens were classified as having chronic active hepatitis (63%), chronic persistent hepatitis (33.8%) or cirrhosis (3.2%). The basal serum levels of iron and ferritin were significantly higher in non responders (126 +/- 9.1 mu/dL and 222.7 +/- 31.9 eta g/dL respectively; p < 0.05) than in responders (101 +/- 5.7 micrograms/dL and 136 +/- 24.1 eta g/dL). Mean transferrin saturation was also higher in nonresponders (29.7% +/- 2.7% vs 26% +/- 2.02%) although this difference was not significant. Younger age, absence of cirrhosis and parenteral transmission were associated with an improved response to interferon therapy. No relationship was found between the presence of iron in the hepatic parenchyma and response to interferon treatment. CONCLUSIONS: elevated serum levels of iron, ferritin, or both may be associated with a worse response to interferon-alpha therapy.

[Intrahepatic cholestasis of pregnancy. Maternofetal implications]. / Colestasis gravídica intrahepática. Implicaciones maternofetales.

OBJECTIVE: To analyze a group of pregnancies complicated by intrahepatic cholestasis in order to favour an early recognition and to decrease maternal and fetal morbid-mortality. PATIENTS AND METHODS: Retrospective study of 46 pregnancies with intrahepatic gravidic cholestasis between 1990-94. We review the most relevant epidemiologic, clinical and biological features and the obstetric and perinatal results. The study group was compared with 1652 non complicated pregnancies (control group) from the same period of time. The statistic evaluation was made with t Student and chi 2. RESULTS: The incidence was 0.18% (mean age of 27.8 +/- 6.7 years) similar to the control group, and a greater rate of primiparity (p < 0.05) and twin pregnancies (p < 0.001). The most frequent symptom was pruritus, followed by choluria (23.9%) and signs of cutaneous scratching (17.3%). Only 5 patients (10.8%) had jaundice. The GPT was greater than 100 U/1 in 29 cases (63.1%) and the GOT in 17 (37%). In 25 pregnancies (54.3%) the alkaline phosphatase exceeded 600 U/L and 28 (60.8%) had bilirubin normal values. Urinary tract infections (26%) and preterm labor (17.3%) were significantly more frequent (p < 0.001) in patients with intrahepatic cholestasis of pregnancy, as well as induced labor rate and cesarean section percentages (p < 0.001). The neonatal prognosis was significantly worse, with 10 preterm babies, 6 with 5 minutes Apgar score lower than 7, and 3 perinatal deaths. All the patients recovered their normal status after delivery. CONCLUSIONS: In intrahepatic gravidic cholestasis moderate cytolysis, infrequent jaundice and cholestasis can be important. The pregnancies should be considered of high risk, and should be managed aggressively as soon as fetal maturity allows it.

[Retrospective multicenter study of the efficacy of interferon alpha in chronic hepatitis C]. / Estudio multicéntrico retrospectivo de la eficacia del interfeón alfa en la hepatitis crónica C.

BACKGROUND: Until very recently, interferon (INF) in Spain was authorized in chronic hepatitis C (C-HCV) at a dosis of 3 megaunits (mu) for 6 months. Nonetheless, the rate of maintained complete response is lower than that obtained with more prolonged treatments. The first aim of this study was to retrospectively know the effectiveness of alpha INF in patients treated for 6 or 12 months with a dosis of 3 or 5-6 MU. The second was to analyze the characteristics of the patients who achieved a maintained complete response. PATIENTS AND METHODS: Patients with C-HCV treated in 9 hospitals in Andalucía, Spain who fulfilled the following conditions were retrospectively analyzed: liver biopsy prior to treatment, positive test for anti HCV and a follow up of at least 6 months after alpha INF treatment. A total of 344 patients were studied: 267 treated with alpha INF-2b, 51 with alpha INF-2a and 26 with lymphoblastoid INF. One hundred ninety-five patients were treated for 6 months and 149 for 12 months. RESULTS: Seventy-seven (22%) of the patients presented maintained complete response, 170 (50%) did not respond and 97 (28%) relapsed. On comparing the three types of interferon used over 6 months, no significant differences were observed. Neither were differences found on comparing the dosis of 3 mu versus 5 or 6 mu. On analyzing the treatments of 6 and 12 months, the following was observed, respectively: maintained complete response 15% vs 32%, relapse 29% vs 30% and non responders 57% vs 38% (p < 0.001). Multivariate analysis demonstrated that the patients who responded the best to INF were those who presented the following characteristics: female sex, age under 40 years last, history of transfusion or IVDA, basal GPT level higher than 145 IU/I, GGT less than 55 IU/I, less evolved histologic lesions and duration of treatment over 12 months. CONCLUSIONS: Of the different treatments analyzed with alpha interferon in chronic hepatitis C, the best was found to be that with 3 mu during 12 months.

[Comparison of the indexes of serologic activity with endoscopy in intestinal inflammatory disease]. / Comparación de los índices de actividad serológicos con la endoscopia en la enfermedad inflamatoria intestinal.

The correlation of the most commonly used clinical and serologic parameters in clinical practice were studied with an endoscopic model for inflammatory bowel disease (IBD). Eighty patients diagnosed with IBD with colic involvement (40 patients with ulcerous colitis [UC] and 40 with Crohn's disease [CD]) were prospectively studied. The CDAI was used as a clinical index of activity in the cases of CD and the True-love and Witts index was used in those with UC. The analytical parameters studied were erythrocyte sedimentation rate (ESR), hemoglobin (Hb), platelets (Th), iron (Fe), protein-C-reactive (PCR), albumin (Ab), orosomucoid (Oro), and alpha-1-antitrypsin (AAT). An excellent correlation was found in the UC in both the clinical index and serologic parameters. However, the correlation in CD was poor and only significant with iron and albumin.

[Thyroid dysfunction in patients with chronic hepatitis C pre and post treatment with interferon]. / Disfunción tiroidea en pacientes con hepatitis crónica C pre y post tratamiento con interferón.

OBJECTIVE: The aim of this study was to evaluate the thyroid function and the dysfunction after interferon therapy in patients with chronic hepatitis C. MATERIAL AND METHODS: Between 1988 and 1994, 119 patients with chronic hepatitis C treated with interferon were reviewed 92 patients received interferon alfa for six or twelve months. 27 patients were treated with interferon beta for six months. Before, during and after interferon therapy, free thyroxine, thyroid-stimulating hormone, antimicrosomal antibodies and antithyroglobulin antibodies were measured in 51 patients. None of the patients had abnormal thyroid function or autoimmune disease before treatment. RESULTS: Among the interferon-treated patients, 6% developed biochemical evidence of thyroid dysfunction during or after therapy. Most cases had hypothyroidism. Thyroid dysfunction was statistically more frequent in the female sex, older patients and in patients who received greater total dose of interferon. In one patient the titters of antimicrosomal thyroid antibodies increased from 1/10 to 1/40 and another patient was positive in a dilution of 1/80 by the time of onset of thyroid disease. Thyroid disease (hypothyroidism) developed in (3.5%) of untreated patients with chronic hepatitis C. CONCLUSIONS: Interferon therapy can development autoimmune thyroid fenomena. Thyroid dysfunction and the presence of antithyroid antibodies before therapy can be a contraindication to the use of interferon in these patients. It is important that patients undergoing interferon therapy be tested for antithyroid antibodies and thyroid function before treatment and be monitored during the course of therapy. Also, it is important to evaluate the factors related with the development of thyroid dysfunction (age, sex, interferon dose...).

[Laparoscopic diagnosis of hepatic angiomas after erroneous imaging techniques]. / Diagnóstico laparoscópico de angiomas hepáticos tras error por técnicas de imagen.

Hemangiomas are de most frequent benign liver tumours. Their clinical relevance is small but they can cause to the patient and/or the physician a great worry because can be indistinguishable from hepatic malignances. From 1991 to 1994 five patients with liver hemangiomas were diagnosed by laparoscopy after a erroneous and/or contradictory interpretation by various imaging techniques. In four cases hemangiomas resembled metastatic carcinoma of the liver, and in the other patient hemangioma was interpreted as focal nodular hyperplasia. Diagnosis and treatment are discussed.

[Emergency laparoscopy. A 20-year experience]. / Laparoscopia de urgencia. Experiencia de 20 años.

We revised 7988 laparoscopies over twenty years. Three hundred and ninety three were urgent laparoscopies: 325 patients with acute spontaneous abdomen and 68 acute traumatic abdomen. Emergency laparoscopy is made in patients with, both spontaneous and traumatic acute abdomen, when diagnosis is not made in 8 hours with the usual clinical and imaging methods. Acute diffuse peritonitis was the commonest finding in the first group (21%) and splenic rupture in the traumatic group (34%). There were two severe complications (0.5%): pulmonary oedema in a patient with myocardial disease and a respiratory failure in a old patient, which were resolved. We had two deaths related to laparoscopic diagnosis: massive mesenteric thrombosis and fecal peritonitis. There are few contraindications and tolerance is very good. This study shows a sensitivity of 98%, a specificity of 90%, a predictive positive value greater than 98% and a negative predictive value of 100%. In summary, the present study demonstrates that emergency laparoscopy is a effective diagnostic method in acute abdominal pain of uncertain aetiology.

[Caroli's syndrome: a variable entity]. / Síndrome de Caroli: una entidad variable.

We present the case of a 56 year old woman with Caroli's disease associated to congenital liver fibrosis, renal nephrocalcinosis and cutaneous vasculitis of the legs. Clinical signs of portal hypertension were treated by a shunt technique. After an asymptomatic period, the patient suffers now from crisis of angiocholitis.

[The effect of environmental factors in inflammatory bowel disease]. / Influencia de factores ambientales en la enfermedad inflamatoria intestinal.

In an attempt to elicit risk factors in inflammatory bowel disease in Spain, we have carried out a case-control study in which we conducted personal interviews asking marital status, place of residence, economic status, use of tobacco and contraceptives, and the method of lactation in infancy. IBD was more common in patients with a low economic level; UC was predominantly found in rural population. No differences were found in the remaining categories. Our results differ from those reported from North and Central Europe.