Recurrent drug-induced liver injury (DILI) with different drugs in the Spanish Registry: the dilemma of the relationship to autoimmune hepatitis.

BACKGROUND & AIMS: Multiple instances of DILI in the same patient with drugs of similar structure or function as well as completely unrelated drugs are not well understood and poorly documented. We have sought evidence of the frequency and characteristics of patients who have experienced two DILI episodes due to different drugs. METHODS: All cases of DILI systematically collected in the Spanish DILI Registry between 1994 and 2009 were retrieved. Data on demographics, clinical, laboratory and pathological findings, and outcome were analyzed. RESULTS: Nine patients (mean age 67 years, four women) out of 742, 1.21%, had evidence of two DILI episodes caused by different drugs. In four cases DILI was associated with structurally related drugs and in an additional two cases the drugs had a common target. In another case, unrelated antibiotics were implicated. In only two cases, the two drugs/herbals were not related in structure or function. All but one patient exhibited hepatocellular damage. The type of damage was consistent in both DILI episodes. Four cases presented as autoimmune hepatitis (AIH) in the second episode. CONCLUSIONS: Multiple episodes of DILI in association with different drugs occur infrequently. In each individual, the type of injury was similar during the two DILI episodes, regardless of the causative drug. Second episodes of DILI are more likely to be associated with features of AIH. It remains uncertain if this is drug-induced unmasking of true AIH or DILI with autoimmune features. These cases illustrate the dilemma faced by clinicians in distinguishing these possibilities.

[Utility of various non-invasive methods for fibrosis prediction among Basque Country patients with phenotypic hemochromatosis]. / Utilidad de los diferentes métodos no invasivos de predicción de fibrosis hepática en pacientes del País Vasco con hemocromatosis fenotípica.

OBJECTIVE: To determine whether the product of multiplying age by liver iron concentration (LIC) (fibrosis index; cut-off, 480,000), platelets, transaminases, and ferritin values are related to the risk of high grade fibrosis. METHODS: A retrospective study of 32 patients with hereditary hemochromatosis (HH) with phenotypic expression. All patients had a liver biopsy with LIC. RESULTS: In 7 patients a magnetic resonance imaging (MRI) scan (1.5 T) was obtained with LIC following Alustiza's protocol. Liver biopsy: fibrosis grade (F) 0-2 in 23 patients; F 3-4 in 9. Fibrosis index (FI) showed a specificity of 68%, sensitivity of 85.7%, positive predictive value (PPV) of 42.8%, and negative predictive value (NPV) of 94.4% for high-grade fibrosis. Platelet count ( < 200,000) revealed a NPV of 94.7% for F3-4. Aspartate transaminase (AST) levels above the upper limit of normal showed a NPV of 94.4%; ferritin levels (> 1,000) a NPV of 75%, and MRI-derived LIC x age (> 480,000) a NPV of 80%. The combination of FI (either by biopsy or MRI) with transaminases, and of platelets with transaminases revealed a NPV of 100%. CONCLUSIONS: FI > 480,000 and platelets < 200,000 have the highest sensitivity for high-degree fibrosis prediction. A negative result allows to discard significant fibrosis in 94% of cases. MRI allows a good fibrosis prediction.

[Porphyria cutanea tarda. An analysis of HFE gene mutations, hepatitis viruses, alcohol intake, and other risk factors in 54 patients from Guipúzcoa, Basque Country, Spain]. / Porfiria cutánea tarda: asociación con mutaciones HFE, hepatitis virales, alcohol y otros factores de riesgo en Guipúzcoa, País Vasco.

AIM: To study the frequency of HFE gene mutations (C282Y, H63D, S65C) in a group of 54 sporadic PCT patients and in a group of healthy controls (blood donors) from Guipúzcoa, Spain. We studied the association of PCT with HCV, HBV, alcohol abuse, and other established risk factors. METHODS: The analysis of mutations was made by PCR. Allelic and genotypic frequencies were compared. Probability was determined and a Chi-squared test was performed. RESULTS: No association was observed between C282Y mutation and PCT (5.76 vs. 5% in controls). A high H63D mutation frequency was observed in PCT (34.25%) but was not statistically significant (controls 29.31%) because of the high prevalence of this mutation in the Basque general population. The S65C mutation was lower in PCT than in controls. There is a similar presence for H63D heterozygosis in PCT (38.8 vs. 38.8%). HCV association was observed in 35.18% of patients with PCT. HBV infected 7.4% of patients. Heavy alcohol intake (> 60 g/day) was present in 55.55% of patients. No HIV-infected patients were detected. The study of other risk factors revealed only one of the five women with PCT taking estrogens. CONCLUSION: Our results found no relevant role for C282Y and H63D mutations. External factors such as HCV and alcohol could be determinant in the development of PCT in the Basque population.

Prevalence of coeliac disease in unexplained chronic hypertransaminasemia.

OBJECTIVE: To determine the prevalence of coeliac disease amongst the population with unexplained chronic hypertransaminasemia in our region. PATIENTS AND METHODS: A prospective study was carried out on 147 consecutive patients with chronic hypertransaminasemia, having previously discarded alcoholic cause, hepatotoxic drugs, B, C and Delta viral infections, autoimmune hepatitis, primary biliary cirrhosis, Jemochromatosis, alfal-antitrypsin deficiency, Wilson's disease, congestive liver and illicit drug use. Serum Ig A to gliadin and endomysium antibodies were determined. Intestinal biopsy was carried out in cases those positive for one or both antibodies. RESULTS: One patient was positive for both IgA to gliadin and to endonisyum antibodies, whereas another three patients were positive to IgA to gliadin only. A duodenal biopsy proved normal in two, a total villous atrophy in one and subtotal atrophy in other. CONCLUSIONS: 1. The prevalence of coeliac disease amongst the population with unexplained chronic hypertransaminasemia in our region is 1.4%. 2. In our region, screening for coeliac disease in unexplained chronic hypransaminasemia should take a secondary place.

Utilidad de los diferentes métodos no invasivos de predicción de fibrosis hepática en pacientes del País Vasco con hemocromatosis fenotípica / No disponible

Objetivo: determinar si el producto de la edad por la concentraciónde hierro hepático (índice de fibrosis) y los valores de plaquetas,ferritina y transaminasas están relacionados con el riesgode padecer fibrosis avanzada (F >= 3) en hemocromatosis.Métodos: estudio retrospectivo de 32 pacientes con hemocromatosishereditaria con expresión fenotípica. Todos los pacientesfueron biopsiados obteniéndose la concentración de hierrohepático.Resultados: en 7 pacientes se realizó RM (1,5T) con obtenciónde concentración de hierro hepático (protocolo de Alustiza).Biopsia hepática: en 23 pacientes fibrosis 0-2; en 9 fibrosis 3-4.El índice de fibrosis mostró una especificidad del 68%, sensibilidaddel 85,7%, VPP del 42,8% y VPN del 94,4% para fibrosis avanzada.La cifra de plaquetas (< 200.000) reveló un VPN 94,4%,ferritina (> 1.000) VPN 75% y el índice de fibrosis por RMN (puntocorte 480.000) VPN 80%. La combinación de los mismos, elíndice de fibrosis (por biopsia o por RM) con las transaminasas ylas plaquetas con las transaminasas, reveló un VPN del 100%.Conclusiones: el índice de fibrosis (> 480.000) y las plaquetas(< 200.000) tienen la mayor sensibilidad para predecir fibrosisde alto grado. Un resultado negativo en ambos permite descartarfibrosis significativa en el 94% de los casos. La RM permite unabuena predicción de fibrosis

Objective: to determine whether the product of multiplyingage by liver iron concentration (LIC) (fibrosis index; cut-off,480,000), platelets, transaminases, and ferritin values are relatedto the risk of high grade fibrosis.Methods: a retrospective study of 32 patients with hereditaryhemochromatosis (HH) with phenotypic expression. All patientshad a liver biopsy with LIC.Results: in 7 patients a magnetic resonance imaging (MRI)scan (1.5 T) was obtained with LIC following Alustiza’s protocol.Liver biopsy: fibrosis grade (F) 0-2 in 23 patients; F 3-4 in 9. Fibrosisindex (FI) showed a specificity of 68%, sensitivity of 85.7%,positive predictive value (PPV) of 42.8%, and negative predictivevalue (NPV) of 94.4% for high-grade fibrosis. Platelet count(< 200,000) revealed a NPV of 94.7% for F3-4. Aspartatetransaminase (AST) levels above the upper limit of normal showeda NPV of 94.4%; ferritin levels (> 1,000) a NPV of 75%, andMRI-derived LIC x age (> 480,000) a NPV of 80%. The combinationof FI (either by biopsy or MRI) with transaminases, and ofplatelets with transaminases revealed a NPV of 100%.Conclusions: FI > 480,000 and platelets < 200,000 havethe highest sensitivity for high-degree fibrosis prediction. A negativeresult allows to discard significant fibrosis in 94% of cases.MRI allows a good fibrosis prediction

Porfiria cutánea tarda: asociación con mutaciones HFE, hepatitis virales, alcohol y otros factores de riesgo en Guipúzcoa, País Vasco / No disponible

Objetivo: estudiar la frecuencia de las mutaciones en el genHFE (C282Y, H63D, S65C) en un grupo de 54 pacientes conporfiria cutánea tarda (PCT) y en un grupo de controles sanos (donantesde sangre) en Guipúzcoa. También analizar su relación conlos virus de la hepatitis B y C (VHB, VHC), alcohol y otros factoresde riesgo reconocidos.Métodos: el análisis de las mutaciones se hizo mediante PCR.Se compararon las frecuencias alélicas y genotípicas. Se determinaronla probabilidad y el test de Chi cuadrado.Resultados: no encontramos asociación entre C282Y y PCT(5,76 vs. 5% controles). Se observó una alta frecuencia alélica enla mutación H63D en PCT (34,25%), pero sin ser estadísticamentesignificativa (controles 29,31%), debido a la alta prevalencia deesta mutación en la población vasca. La mutación S65C fue menoren PCT que en controles. Encontramos una idéntica presenciade H63D en heterocigosis en ambos grupos (38,8 vs. 38,8%).La asociación con el VHC se objetivó en el 35,18% de los pacientesy la infección por VHB en el 7,4%. Un 55,55% de los pacientestenía un hábito alcohólico de más de 60 g etanol día. Todoseran negativos para el virus de la inmunodeficiencia humana (VIH)y 1 de las 5 mujeres con PCT tomaba estrógenos.Conclusión: las mutaciones C282Y y H63D no tienen un papelrelevante en los pacientes con PCT en Guipúzcoa. Los factoresexternos (consumo importante de alcohol y VHC) parecen jugarun papel fundamental en el desarrollo de la PCT en nuestrapoblación

Aim: to study the frequency of HFE gene mutations (C282Y,H63D, S65C) in a group of 54 sporadic PCT patients and in agroup of healthy controls (blood donors) from Guipúzcoa, Spain.We studied the association of PCT with HCV, HBV, alcohol abuse,and other established risk factors.Methods: the analysis of mutations was made by PCR. Allelicand genotypic frequencies were compared. Probability was determinedand a Chi-squared test was performed.Results: no association was observed between C282Y mutationand PCT (5.76 vs. 5% in controls). A high H63D mutationfrequency was observed in PCT (34.25%) but was not statisticallysignificant (controls 29.31%) because of the high prevalence ofthis mutation in the Basque general population. The S65C mutationwas lower in PCT than in controls. There is a similar presencefor H63D heterozygosis in PCT (38.8 vs. 38.8%). HCV associationwas observed in 35.18% of patients with PCT. HBVinfected 7.4% of patients. Heavy alcohol intake (> 60 g/day) waspresent in 55.55% of patients. No HIV-infected patients were detected.The study of other risk factors revealed only one of the fivewomen with PCT taking estrogens.Conclusion: our results found no relevant role for C282Yand H63D mutations. External factors such as HCV and alcoholcould be determinant in the development of PCT in the Basquepopulation

Prevalecencia de enfermedad celíaca en la hipertransaminasemia crónica de causa no conocida / Prevalence of coeliac disease in unexplained chronic hypertransaminasemia

Objetivo: determinar la prevalencia de celiaquía en la hipertransaminasemia crónica de causa desconocida de nuestro medio. Pacientes y métodos: estudio transversal en 147 pacientes consecutivos con hipertransaminasemia crónica a los que previamente se había descartado etiología alcohólica, medicamentosa, vírica B, C y delta, autoinmune, cirrosis biliar primaria, hemocromatosis, déficit de alfa1 antitripsina, enfermedad de Wilson, hígado congestivo y drogadicción. Se determinaron anticuerpos antiendomisio y antigliadina de tipo Ig A a todos los pacientes. La biopsia intestinal se realizó en los casos positivos para uno o ambos anticuerpos y en aquellos casos en los que la sospecha clínica lo aconsejaba, a pesar de la negatividad de ambos anticuerpos. Resultados: se detectó un caso con anticuerpos antiendomisio y antigliadina positivos y tres con positividad exclusivamente para los antigliadina. La biopsia intestinal fue normal en dos de estos casos y patológica en los otros dos, con atrofia villosa total en uno y subtotal en el otro. Conclusiones: 1. La prevalencia de celiaquía en la población con hipertransaminasemia crónica de causa no conocida de nuestro medio es de 1,4 por ciento.2. Dada la baja prevalencia en nuestro medio, el cribado de celiaquía en la población con hipertransaminasemia crónica, debería ocupar un segundo lugar y realizarse de forma simultánea con el resto de causas poco comunes (AU)