Search

[Background & Aims] Prospective drug-induced liver injury (DILI) registries are important sources of information on idiosyncratic DILI. We aimed to present a comprehensive analysis of 843 patients with DILI enrolled into the Spanish DILI Registry over a 20-year time period., [Methods] Cases were identified, diagnosed and followed prospectively. Clinical features, drug information and outcome data were collected., [Results] A total of 843 patients, with a mean age of 54 years (48% females), were enrolled up to 2018. Hepatocellular injury was associated with younger age (adjusted odds ratio [aOR] per year 0.983; 95% CI 0.974–0.991) and lower platelet count (aOR per unit 0.996; 95% CI 0.994–0.998). Anti-infectives were the most common causative drug class (40%). Liver-related mortality was more frequent in patients with hepatocellular damage aged ≥65 years (p = 0.0083) and in patients with underlying liver disease (p = 0.0221). Independent predictors of liver-related death/transplantation included nR-based hepatocellular injury, female sex, higher onset aspartate aminotransferase (AST) and bilirubin values. nR-based hepatocellular injury was not associated with 6-month overall mortality, for which comorbidity burden played a more important role. The prognostic capacity of Hy’s law varied between causative agents. Empirical therapy (corticosteroids, ursodeoxycholic acid and MARS) was prescribed to 20% of patients. Drug-induced autoimmune hepatitis patients (26 cases) were mainly females (62%) with hepatocellular damage (92%), who more frequently received immunosuppressive therapy (58%)., [Conclusions] AST elevation at onset is a strong predictor of poor outcome and should be routinely assessed in DILI evaluation. Mortality is higher in older patients with hepatocellular damage and patients with underlying hepatic conditions. The Spanish DILI Registry is a valuable tool in the identification of causative drugs, clinical signatures and prognostic risk factors in DILI and can aid physicians in DILI characterisation and management., [Lay summary] Clinical information on drug-induced liver injury (DILI) collected from enrolled patients in the Spanish DILI Registry can guide physicians in the decision-making process. We have found that older patients with hepatocellular type liver injury and patients with additional liver conditions are at a higher risk of mortality. The type of liver injury, patient sex and analytical values of aspartate aminotransferase and total bilirubin can also help predict clinical outcomes., The present study has been supported by grants of Instituto de Salud Carlos III cofounded by Fondo Europeo de Desarrollo Regional – FEDER (contract numbers: PI19/00883, PI16/01748, PI18/00901, PI18/01804, PI-0285-2016, PI-0274-2016, PI-0310-2018, PT17/0017/0020) and Agencia Española del Medicamento. CIBERehd and Plataforma ISCIII Ensayos Clinicos are funded by Instituto de Salud Carlos III. MRD holds a Joan Rodes (JR16/00015)/Acción B clinicos investigadores (B-0002-2019) and JSC a Rio Hortega (CM17/00243) research contract from ISCIII and Consejería de Salud de Andalucía.

Background and Aims. There are limited data on clinical and phenotypic characteristics of outpatients referred for hyperferritinemia (HF). To determine the causes of HF in outpatients referred to a secondary hospital.Material and methods. A prospective study of 132 consecutive patients with HF (> 200 μg/L, women; > 300 μg/L, men) was conducted from January-December 2010.Results. Mean age, 54.42 years (SD: 13.47, range: 23-83); body mass index (BMI), 28.80 (SD: 3.96, 17-39); ferritin (SF), 579.54 ng/mL (SD: 296.575, 206-1668); transferrin saturation (TSI), 43.87% (SD: 14.09, 12-95); iron (Fe), 134 μg/dL (SD: 49.68, 55-322); overweight: 48.31%, and obese: 40.44% (89%), and most patients were men (108/132). Regarding HFE mutations, H63D/H63D genotype and H63D allele frequencies were 17.5% (vs. 7.76% in controls); and 36% (31% in controls) respectively. While 63.6% consumed no alcohol, 18.1% consumed ≥ 60 g/day, the mean being 20.83 (SD: 33.95, 0-140). Overall, 6/132 (4.5%) patients were positive for B or C hepatitis. Mean LIC by MRI was 36.04 (SD: 32.78, 5-210), 53 patients having normal concentrations (< 36 µmol/g), 22 (33%) iron overload (37-80), and 4 (5%) high iron overload (> 80). Metabolic syndrome (MS) was detected in 44/80 men (55%) and 10/17 women (59%). In this group, the genotype frequency of the H63D/H63D mutation was significantly higher than in controls-21.56% vs. 7.76%- (p = 0.011); the H63D allelic frequency was 42.15% in MS group and 31% in controls (p = 0.027).Conclusion. The H63D/H63D genotype and H63D allele predispose individuals to HF and MS. MRI revealed iron overload in 33% of patients.

Background & aims. Hyperferritinemia (HF) is frequently present in patients with metabolic syndrome (MS). MS associated with HF is named dysmetabolic hyperferritinemia (DH). There are some publications that propose that DH is associated with a raised liver iron concentration (LIC). We studied the LIC in patients referred for HF to a secondary hospital to determine if there are differences between patients with or without MS.Material and methods. We conducted a prospective study of 132 consecutive patients with HF from January to December 2010. The MS was defined by the International Diabetes Federation criteria (2005). LIC was determined by Magnetic resonance imaging (MRI).Results. The number of patients for which there was enough data to determine MS was 97, out of which 54 had MS and 43 had no MS (NMS). In 54/97 patients, MRI for LIC determination was performed. From the MS group, 44 were men (27 underwent MRI) and 10 women (9 MRI). The mean LIC was 27.83 ± 20.90 μmol/g for the MS group. In the NMS group, 36 were men (13 MRI), and 7 women (5 MRI). In 18 patients from the NMS group, LIC was determined by MRI. The mean LIC was 33.16 ± 19.61 μmol/g in the NMS group. We compared the mean values of LIC from both groups (MS vs. NMS) and no significant differences were found (p = 0.067).Conclusion. Patients with DH present a mean LIC within normal values and their values do not differ from those of patients with HF but without MS.

Background: Olynyk et al. studied the liver iron concentration (LIC) by MRI of 52 consecutive patients of northern European origin who were referred to a tertiary hospital for hyperferritinemia (HF). They described three groups according to HFE mutations and the transferrin saturation index (TSI) (group A: no predisposing mutations (PM) for hereditary hemochromatosis (HH) and TSI > 45 %, group B: PM for HH and TSI > 45 %; group C: no PM for HH and normal TSI). In the Basque country, HH predisposing mutations differ, with prevalence of the H63D/H63D mutation. Objectives: To study the importance of HFE mutations and the TSI in determining LIC of HF patients attending the outpatient clinic at a secondary hospital. Methods: Prospective study of 132 consecutive patients with HF. In 120 HFE study was available. In 79 LIC was obtained by MRI. In 71 patients values of HFE mutations, TSI, and LIC by MRI were available. Results: Mean age: 55.68 ± 14.26 (23 - 83), 55 men and 16 women. The mean LIC in men was 35.66 ± 36.85; women 38.81 ± 29.75. The mean LIC in group A: 38.80 ± 45.18 (5 - 210), group B: 48.96 ± 37.51 (15 - 160), group C: 28.12 ± 18.85 (5 - 75). We compared the LIC mean values of the 3 groups with no significant differences. Conclusions: LIC values are similar in different groups of patients referred to a secondary hospital for HF, despite variable predisposition to HH.

There is a lack of prospective studies evaluating the natural history of colonic ischaemia (CI). We performed such a study to evaluate the clinical presentation, outcome, and mortality as well as clinical variables associated with poor prognosis.An open, prospective, and multicentre study was conducted in 24 Spanish hospitals serving a population of 3.5 million people. The study included only patients who met criteria for definitive or probable CI. A website (www.colitisisquemica.org) provided logistical support.A total of 364 patients met criteria for inclusion. CI was suspected clinically in only 24.2% of cases. The distribution of clinical patterns was as follows: reversible colopathy (26.1%), transient colitis (43.7%), gangrenous colitis (9.9%), fulminant pancolitis (2.5%), and chronic segmental colitis (17.9%). A total of 47 patients (12.9%) had an unfavorable outcome as defined by mortality and/or the need for surgery. Multivariate analysis identified the following signs as independent risk factors for an unfavorable outcome: abdominal pain without rectal bleeding [odds ratio (OR) 3.9; 95% confidence interval (CI) = 1.6-9.3], non-bloody diarrhoea (OR 10; 95% CI = 3.7-27.4), and peritoneal signs (OR 7.3; 95% CI = 2.7-19.6). Unfavorable outcomes also were more frequent in isolated right colon ischaemia (IRCI) compared with non-IRCI (40.9 vs. 10.3%, respectively; p0.0001). The overall mortality rate was 7.7%.The clinical presentation of CI is very heterogeneous, perhaps explaining why clinical suspicion of this disease is so low. The presence of IRCI, and occurrence of peritoneal signs or onset of CI as severe abdominal pain without bleeding, should alert the physician to a potentially unfavorable course.

Background: The significance of H63D homozygosity remains uncertain, although it is associated with a tendency for patients to develop iron overload. Aims: To study the prevalence of homozygotic H63D mutation in patients with phenotypic hemochromatosis (PH) and to compare the results with those of the general population and with patients with porphyria cutanea tarda (PCT) in the Basque Country, Spain. A secondary aim was to evaluate the differences in phenotypic expression and liver injury according to different genotypes in the PH cohort. Methods: Mutations of the HFE gene were obtained by polymerase chain reaction (PCR). Forty consecutive patients diagnosed with PH, 116 controls and 54 patients with PCT were included in the study. We performed liver biopsies, measured liver iron concentration (LIC), by atomic spectrophotometry, serum ferritin and transferrin saturation, and compared the histology according to the genotype. Results: The H63D homozygote mutation was identified in 7.76% of the control group, in 7.50% of the PH group, and in 11.11% of patients with PCT (P > 0.05). The C282Y/C282Y mutation was present in 50% of patients with PH, and LIC was identified in 15/20. The LIC in C282Y/C282Y patients was higher than in H63D/H63D patients (P = 0.26), while H63D homozygosis caused greater iron overload in PH patients than other genotypes. All the C282Y/C282Y genotype patients had elevated serum ferritin and transferrin saturation. The H63D homozygotes had high ferritin, but two out of three had normal transferrin saturation. Six of the eight patients with high-grade fibrosis and genetic study results were found to be C282Y/C282Y. Conclusions: The prevalence of H63D mutation in patients with PH in our region does not differ from that of the general Basque population.

Objectives Positive autoantibody (AAB) titres are commonly encountered in autoimmune hepatitis (AIH) and in a proportion of drug-induced liver injury (DILI) patients. The underlying mechanism for selective AAB occurrence in DILI is unknown, but could be associated with variations in immune-associated genes. Hence, we aimed to analyse human leucocyte antigen (HLA) allele compositions in DILI with positive (+) and negative (-) AAB titres and in AIH patients. Methods High-resolution genotyping of HLA class I (A, B, C) and II (DRB1, DQB1) loci was performed on 207 DILI and 50 idiopathic AIH patients and compared with 885 healthy Spanish controls. Results Compared with controls, HLA-B*08:01 [ 44 vs. 9.7%, P = 3.7E-13/corrected P-value (P-c) = 1.0E-11], C*07:01 (46 vs. 24%, P = 6.4E-04/P-c = 0.012), DRB1*03:01 (58 vs. 21.5%, P = 5.0E-09/P-c = 1.0E-07) and DQB1*02:01 (56 vs. 22%, P = 6.8E-08/P-c = 9.0E-07) were significantly more frequent in AIH patients. The HLA-A*01:01 frequency was increased in the same population, but did not reach significance after Bonferroni's correction (34 vs. 19%, P = 0.02/P-c = 0.37). Fifty-eight of 207 DILI patients presented positive titres for at least one AAB (predominantly antinuclear antibody 76% and antismooth muscle antibody 28%). There was a tendency towards higher representation of DRB1*14:01 and DQB1*05:03 in DILI AAB(+) compared with DILI AAB- (13.8 vs. 4.0%, P = 0.02/P-c = 0.5; 13.8 vs. 4.7%, P = 0.04/P-c = 0.5). Conclusion The presence of HLA alleles B*08:01, C*07: 01, DRB1*03: 01, DQB1*02: 01 and possibly A*01: 01 enhances the risk of AIH (type 1) in Spanish patients. These alleles form part of the ancestral haplotype 8.1. HLA-DRB1*14:01 and DQB1*05: 03 could potentially increase the risk of positive AAB (particularly antinuclear antibody) in Spanish DILI patients. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

Dear Editor,We have read with interest the excellent review byCzaja [1] titled ‘‘Drug-Induced Autoimmune-Like Hepati-tis’’. We would like to add some comments to highlight thecomplexities faced when approaching a diagnosis of thisdisorder.Firstly, it is stated under the subheading ‘‘Drug-InducedHepatitis Within the Spectrum of Immune-Mediated Hep-atitis’’ that the best estimate of the frequency of drug-induced autoimmune-like hepatitis (AIH-DILI) amongpatients with classical features of autoimmune hepatitis is9% [2]. To our knowledge, there are other reports thatshow higher figures. Heurgue´ et al. [3] in France identifiedin a consecutive series of 65 patients with autoimmunehepatitis (AIH) eight cases (12%) with drug-induced AIH,fulfilling all requirements recommended in the review toconfirm the diagnosis. In Gipuzkoa (Deba Valley, totalcatchment of 140,000 people), Spain, from 1994 to 2009,29 cases of AIH were diagnosed, and five were consideredas AIH-DILI, which represents 17% [4]. We think thatthese differences in frequency may be explained by the factthat AIH-DILI is often misdiagnosed. Indeed, the diagnosisof AIH is often made in the setting of a patient beingtreated with multiple drugs. If the diagnostic scale indicatesa probable AIH, the possible role of the drug is generallyunderscored, and immunosuppressive treatment is started.On the other hand, if the AIH scale is not conclusive and/orhistology findings are more consistent with drug-inducedliver injury (DILI), the case is assumed to be an AIH-DILIcase, particularly if after discontinuation of the suspecteddrug the clinical symptoms resolve (AIH-DILI may be aself-limiting process), and the possibility of unmaskingAIH by the action of a drug is subsequently disregarded. Tofurther complicate the differentiation between AIH andDILI, we must underline the fact that there does not seemto be any specific histological features for either of theprocesses and the pathological features may show onlysubtle differences, pointing toward an immune mediatesliver disease versus hepatic toxicity [5]. These consider-ations lead us to suggest that AIH-DILI might be under-reported nowadays.Secondly, it is said that most drugs produce a self-lim-ited acute hepatitis, which is unusual in true AIH [1], butthat others seem to trigger a chronic hepatitis that isindistinguishable from classical AIH. In a recent study,Bjo¨rnsson et al. [2] published 24 cases of AIH-DILI, 22being minocycline and nitrofurantoin cases (11/11). Dis-continuation of steroid therapy was tried in 14 cases, withno relapses. Of the AIH cases in this series, 65% relapsed.In a French series [3], one patient had a spontaneous

A cohort study of patients included in the Basque Country colorectal cancer (CRC) screening programme was carried out to assess the risk of adenomatous polyps and CRC (P-CRC) associated with HFE gene mutations, with gender and with iron biomarkers (serum ferritin (SF), iron (Fe) and transferrin saturation index (TSI)). Among 432 included patients (mean age 59.8 years), 263 were men (60.9 %) and 169 women (39.1 %). P-CRC were identified in 221 patients (51.2 %) and no polyps (NP) in 211 patients (48.8 %). HFE mutations were identified in 43.8 % of the patients. C282Y/wt genotypic frequency was 6.8 % in the P-CRC group and 1.4 % in the NP group (p

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 67years, 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.

The significance of H63D homozygosity remains uncertain, although it is associated with a tendency for patients to develop iron overload.To study the prevalence of homozygotic H63D mutation in patients with phenotypic hemochromatosis (PH) and to compare the results with those of the general population and with patients with porphyria cutanea tarda (PCT) in the Basque Country, Spain. A secondary aim was to evaluate the differences in phenotypic expression and liver injury according to different genotypes in the PH cohort.Mutations of the HFE gene were obtained by polymerase chain reaction (PCR). Forty consecutive patients diagnosed with PH, 116 controls and 54 patients with PCT were included in the study. We performed liver biopsies, measured liver iron concentration (LIC), by atomic spectrophotometry, serum ferritin and transferrin saturation, and compared the histology according to the genotype.The H63D homozygote mutation was identified in 7.76% of the control group, in 7.50% of the PH group, and in 11.11% of patients with PCT (P0.05). The C282Y/C282Y mutation was present in 50% of patients with PH, and LIC was identified in 15/20. The LIC in C282Y/C282Y patients was higher than in H63D/H63D patients (P = 0.26), while H63D homozygosis caused greater iron overload in PH patients than other genotypes. All the C282Y/C282Y genotype patients had elevated serum ferritin and transferrin saturation. The H63D homozygotes had high ferritin, but two out of three had normal transferrin saturation. Six of the eight patients with high-grade fibrosis and genetic study results were found to be C282Y/C282Y.The prevalence of H63D mutation in patients with PH in our region does not differ from that of the general Basque population.

To evaluate the accuracy of magnetic resonance (MR) imaging in the quantification of hepatic iron concentration.Between April 1999 and June 2001, 112 patients were recruited prospectively. All had undergone liver biopsy and hepatic iron concentration quantification with spectrophotometry, followed by MR imaging. MR imaging involved use of four gradient-echo sequences and one spin-echo sequence. Signal intensity (SI) was measured on images obtained with each sequence by means of regions of interest placed in the liver and paraspinal muscle to obtain the liver-to-muscle SI ratio. The relationship between hepatic iron concentration and SI ratio for each sequence was analyzed with multiple linear regression. Receiver operating characteristic analysis was performed to find the diagnostic thresholds.Sixty-eight patients had normal hepatic iron levels (36 micromol/g), 23 had hemosiderosis (36-80 micromol/g), and 21 had hemochromatosis (80 micromol/g). With all sequences, an inverse linear relationship between iron concentration and SI ratio was apparent. The authors generated a mathematic model to estimate the iron concentrations from MR imaging data (r = 0.937). For estimated concentrations of more than 85 micromol/g, the positive predictive value for hemochromatosis was 100%; for those less than 40 micromol/g, the negative predictive value for hemochromatosis was 100%. For estimated concentrations of more than 58 micromol/g, the positive predictive value for iron overload was 100%; for those less than 20 micromol/g, the negative predictive value for iron overload was 100%.MR imaging is a useful and noninvasive diagnostic tool for quantification of hepatic iron concentration.

Introduction: Natural history studies show that the risk of development chronic HBV infection is inversely proportional with age of acquisition: 25% of children infected at