Diabetes mellitus: impact on the pathophysiology, diagnose and treatment of the hepatic encephalopathy.

Tesis descargada de TESEOEncefalopatía hepática La encefalopatía hepática (EH) es un disturbio potencialmente reversible, de causa metabólica, que ocurre en pacientes con enfermedad hepática aguda o crónica, y que consiste en una alteración del funcionamiento del sistema nervioso central. Entre el 30%-50% de pacientes cirróticos que no muestran síntomas de EH clínica presentan encefalopatía hepática mínima (EHM). La EHM es la primera alteración dentro del espectro de manifestaciones clínicas del síndro¬me de la EH. Se define como la presencia de defectos cognitivos en pacientes con enfermedad hepática, los cuales no son detectados en la exploración clínica habitual. La prevalencia de EHM oscila entre 25 y 33% de los pacientes cirróticos compensados y se asocia con el desarrollo de EH posterior. En cuanto a su patogénesis, el amonio juega un papel fundamental. Se produce por la deamidación de glutamina por la glutaminasa (GLS) en los enterocitos del intestino delgado y colon, así como a través de la hidrólisis de urea por las bacterias que están en el intestino. En el sistema nervioso central, los astrocitos son las únicas células capaces de metabolizar el amonio, ya que poseen glutamina-sintetasa que se encarga de convertir el glutamato y el amonio en glutamina (que, al ser osmóticamente activa, provoca la entrada de agua en el astrocito, generando edema). Por otro lado, la patofisiología de la EH está íntimamente relacionada con cambios en la barrera hemato-encefálica, a través de la respuesta inflamatoria sistémica. Durante la infección, las células de la microglía se activan y los astrocitos liberan citoquinas proinflamatorias (IL-6, TNF¿), las cuales son capaces de exacerbar las alteraciones neuropsicológicas inducidas por la propia hiperamonemia. Otra característica de TNF¿ es que influye en la permeabilidad de la barrera hemato-encefálica, lo cual favorece la difusión del amonio. De una manera similar, los niveles séricos de IL-6 se correlacionan con la presencia de EHM y su severidad. En este contexto, la diabetes mellitus (DM) y la resistencia a la insulina (RI) podrían tener una especial relevancia en la patogenia de la EH. En primer lugar, DM parece ser capaz de modular GLS. Watford et al. observaron que la actividad de la GLS estaba incrementada en riñón, hígado e intestino delgado de ratas diabéticas. En segundo lugar, DM y RI se caracterizan por la liberación de citoquinas proinflamatorias, particularmente TNF¿ y IL-6, lo que resulta en un incremento de la respuesta inflamatoria sistémica. El diagnóstico de EH es fundamentalmente clínico, mientras que para la EHM no se ha establecido un test estándar. PHES (Psychometric Hepatic Encephalopathy Score) combina cinco test psicométricos, cuya puntuación oscila entre -15 y +3, siendo el lími¬te que define la existencia de EHM -4 puntos. PHES puede ser usado para detectar la mayoría de alteraciones neuropsicológicas relacionadas con EHM, ya que evalúa la velocidad y precisión del movimiento, la percepción visual, la orientación espacial, la concentración, la atención y la memoria. Existe otro grupo de pruebas, clasificadas como neurofisiológicas. La medición de la frecuencia crítica de par¬padeo (FCP) se ha mostrado útil en el diagnóstico de la EHM. Consiste en pulsar un botón cuando el paciente nota que existe parpadeo en un punto luminoso en el in¬terior de unas gafas cerradas. El punto de corte se sitúa en 38 HZ, de manera que valores superiores se consideran normales y valores inferiores, patológicos. Por último, existen las pruebas bioquímicas. La prueba de la sobrecarga oral de glutamina (SOG) consiste en evaluar las concentraciones de amonio, tras la administración oral de glutamina (concentraciones >128 ¿g/dL a los 60 minutos son patológicas). La alteración de esta prueba origina un 25% más de riesgo de desarrollar EH. La lactulosa y el lactitol son los tratamientos de los que existen más datos, ya que han sido usados en práctica clínica desde hace tiempo. La lactulosa es metabolizada por las bacterias colónicas en ácido acético y ácido láctico, los cuales acidifican el medio (reduciendo el pH) y, por consiguiente, impiden el crecimiento de las bacterias productoras de amonio. Este efecto acidificador se suma a su efecto catártico y laxante (eliminando otro posible desencadenante, como es el estreñimiento). Por otro lado, la rifaximina se ha postulado como la mejor alternativa. Se trata de un antibiótico oral de amplio espectro y escasamente absorbible, lo que dificulta la aparición de efectos secundarios y de resistencias. La rifaximina mejora los resultados de los test psicométricos, la calidad de vida y la habilidad en la conducción de pacientes con EHM, así como la prevención de EH. Metformina La metformina es un antidiabético oral del grupo de las biguanidas, que representa un tratamiento de primera línea. Disminuye la glucemia fundamentalmente a través de la inhibición de la gluconeogénesis hepática (a través de la activación de AMP cíclico), disminuye la absorción de glucosa intestinal y aumenta la sensibilidad a insulina en tejidos periféricos. Estudios recientes indican que, además, tiene propiedades antioxidantes, antiinflamatorias, antiangiogénicas y de inhibición del crecimiento, reduciendo el riesgo de algunos tumores sólidos (próstata, colon, mama y páncreas). Las propiedades antiinflamatorias (principalmente, la disminución de citoquinas proinflamatorias y de estrés oxidativo) contribuyen a reducir la respuesta inflamatoria sistémica. Por otro lado, Chen et al. concluyeron que la metformina se asocia a una reducción en el riesgo de CHC, de una manera dosis-dependiente. La capacidad de la metformina para reducir los niveles de insulina y activar AMP cíclico representa, respectivamente, su mecanismo antioncogénico directo e indirecto. Además, se ha propuesto que la reducción de riesgo de CHC por metformina se debe a que: a) la fosforilación de AMP cíclico suprime la vía de señalización de Akt/mTOR, inhibiendo la proliferación celular; b) modula la expresión de citoquinas proinflamatorias, tales como TNF¿ y el estrés oxidativo; c) efectos antiproliferativos y antineoplásicos asociados a la inhibición de mTORC1. 2.- OBJETIVOS ¿ Objetivos primarios: o Evaluar, en la encefalopatía hepática mínima, la importancia de la inhibición de la actividad de la glutaminasa y la disminución de la resistencia a la insulina, mediante la administración de metformina. ¿ Objetivos secundarios: o Evaluar la eficacia y seguridad del tratamiento con metformina en pacientes con cirrosis hepática. 3.- MATERIAL Y MÉTODOS 3.1.-Estudio clínico Pacientes cirróticos y diabéticos tipo 2 de la Unidad de Gestión Clínica de Enfermedades Digestivas serán incluidos en el estudio. El inicio del estudio fue la primera visita a consulta de Hepatología o el primer ingreso hospitalario, y finalizó con el éxitus, el trasplante hepático o la encefalopatía hepática. Los criterios de exclusión fueron: edad inferior a 18 años, pacientes no diabéticos, pacientes diabéticos tipo 1, y pacientes en tratamiento antiviral activo. Los pacientes fueron clasificados en función de su experiencia con los sensibilizadores de insulina. De esta forma, los casos fueron los pacientes que estaban en tratamiento con metformina, mientras que los controles eran los pacientes cirróticos diabéticos que no estaban en tratamiento con metformina, y observamos aquellos que desarrollaban encefalopatía hepática. EHM se diagnosticó según PHES y FCP (HepatonormTM Analyzer (R&R Medi-Business Freiburg GmbH, Freiburg, Alemania). Los pacientes tuvieron EHM si PHES es < 4 o FCP < 38 Hz. Para la SOG, muestras sanguíneas fueron tomadas al inicio y a los 60 minutos tras la ingestión de glutamina (L-Glutamine, SHS S.A., España). El amonio fue medido mediante el método DaFonseca-Whollheim en un autoanalizador (Hitachi 911; Roche Diagnostics, Mannheim, Alemania). Se realizó un estudio genético que incluyó la longitud de microsatélites en la región 5¿UTR del gen de la glutaminasa, junto con el haplotipo TACC, según estudios previos. Además, definimos pacientes con alto riesgo de padecer EHM (PHES < -4 o CFF < 38 Hz), que fueron los que además tenían SOG patológica o desfavorable genética. Para ambos estudios, los análisis basales se realizaron con kits comerciales e incluyeron: insulina, glucosa, glucagón, TNFr2, leptina, adiponectina, AST y ALT. HOMA-IR será calculado [glucosa (mmol/L) * Insulina (IU/ml)/22.5]. El diagnóstico de cirrosis hepática se basó en hallazgos en biopsia hepática, ecografía abdominal, endoscopia oral y parámetros bioquímicos. Diabetes mellitus tipo 2 se diagnosticó según la American Diabetes Association: a) glucosa en ayunas >126 mg/dl; b) glucosa en plasma >200 mg/dl 2 horas después de un test de glucosa oral; y c) glucosa plasmática aleatoria >200 mg/dl en un paciente con síntomas típicos de hiperglucemia. El protocolo de ambos estudios fue aprobado por el comité ético del Hospital Universitario de Valme. 3.2.-Estudio experimental Llevamos a cabo un estudio experimental in vitro (ensayo enzimático y celular) para investigar la inhibición de la actividad de la glutaminasa, en función de diferentes concentraciones de metformina. En primer lugar, en un ensayo enzimático, probamos diferentes concentraciones de metformina (0, 10, 25, 50 and 100µM) con una concentración constante de glutamina (100mM). La producción de amonio se medió para determinar la actividad de la glutaminasa. En segundo lugar, utilizamos una línea celular Caco2 (American Type Culture Collection, ATCC) que fue mantenida en medio DMEM a pH 7.4, suplementado con suero fetal bovino 10%, 2.2 g/L HCO3Na, 100mM de piruvato sódico, 0.292 gr/L glutamina, 100 U/mL penicillina, 100 ¿g/mL estreptomicina y 0.25 ¿g/mL anfotericina, en medio húmedo a 5% CO2 y a 37°C. El ensayo celular se inició 24 horas antes de la siembra. Las células Caco2 (10000 células/cm2) fueron cultivadas en presencia de diferentes dosis de metformina (0, 20, 50, 100 and 200 mM) y se tomaron muestras a las 0, 24, 48 y 72 horas post-tratamiento. La actividad de la glutaminasa fue medida determinando la producción de amonio. 4.- CONCLUSIONES Como se ha observado a través de los diferentes artículos publicados y comunicaciones expuestas en diversos congresos nacionales e internacionales, la metformina es un fármaco útil, barato y seguro en la prevención del desarrollo de encefalopatía hepática en pacientes con cirrosis hepática, a través de la inhibición parcial de la actividad de la glutaminasa.Premio Extraordinario de Doctorado U

COVID-19 and the liver: the chicken or the egg dilema

After the publication of our meta-analysis, in which we demonstrated that aspartate aminotransferase (AST), alanine aminotransferase (ALT) and total bilirubin were related to a poor prognosis in patients suffering COVID-19, some authors raised the question about whether these findings are directly linked, or they are epiphenomena

Looking for a new name for non-alcoholic fatty liver disease in Spanish: esteatosis hepatica metabolica (EHmet)

El nombre de una enfermedad no sigue ningún protocolo definido y es habitual la aceptación por parte de la comunidad científica de diversas variantes en función de las costumbres de cada lugar. Hay ejemplos de entidades prevalentes con curiosos procesos de denominación, como la diabetes mellitus. La primera palabra, "diabetes", proviene del griego dia (a través), be (ir) y tes (factor), mientras que la segunda palabra, "mellitus", proviene del latín melli (miel). En consecuencia, diabetes mellitus significa literalmente "el factor dulce que atraviesa...", perteneciente a una diuresis excesiva y dulce. Por lo tanto, podríamos deducir que no se requiere una definición que represente exactamente la fisiopatología de la enfermedad en particular.The name of a disease does not follow any defined protocol and the scientific community's acceptance of several variants based on the customs of every location is usual. There are examples of prevalent entities with curious naming processes, such as diabetes mellitus. The first word, "diabetes", comes from the Greek dia (through), be (to go), and tes (factor), while the second word, "mellitus", comes from Latin melli (honey). As a consequence, diabetes mellitus literally means "the sweet factor that goes through…", pertaining to an excessive and sweet diuresis. Thus, we could deduce that a definition representing exactly the pathophysiology of the particular disease is not required

Usefulness of bioelectrical impedance analysis for monitoring patients with refractory ascites

Background: bioelectrical impedance analysis is a technique for the determination of the hydropic component. The hydropic component, determined by blood volume, could be a reflection of the hemodynamic situation. This study aimed to evaluate the usefulness of peripheral bioelectrical impedance analysis (BIA) for the prediction of hemodynamic changes in large-volume paracentesis and prognosis. Methods: this was a proof-of-concept prospective study of 14 patients with liver cirrhosis and refractory ascites. Peripheral bioimpedance was measured three times using a portable device, IVOL®, before and after large-volume paracentesis, at different frequencies (5, 10, 20, 50, 100 and 200 kHz). Consequently, resistance, reactance and phase angle were obtained, both pre- and post-paracentesis (the difference between them was defined as Δ). Results: the mean age of patients was 62.2 ± 9.6 years, the Child-Pugh was 8.4 ± 1.3 and the MELD score was 15.2 ± 3.9. A direct correlation between the extraction of ascitic fluid and Δresistance (10 kHz [r = 0.722; n = 12; p = 0.008], 20 kHz [r = 0.658; n = 12; p = 0.020] and 50 kHz [r = 0.519; n = 14; p = 0.057]) was observed. The presence of edema was related to lower values of both pre-paracentesis resistance (10 Hz [23.9 ± 8 vs 32.2 ± 4; p = 0.043]) and phase angle (5 kHz [-1.9 ± 2.8 vs 5.9 ± 7.3; p = 0.032]). Pre-paracentesis phase angle was directly correlated with the decline in blood pressure after paracentesis at lower frequencies (5 kHz [r = 0.694; n = 13; p = 0.008] and 10 kHz [r = 0.661; n = 13; p = 0.014]). Lower frequencies of Δphase-angle impacted on patient prognosis (5 kHz [-8.6 ± 5 vs -2.5 ± 2.7; p = 0.021]), patients with Δphase-angle 5 kHz > -4 had a higher rate of mortality (83.3% [5/6] vs 0% [0/6]; logRank 7.306, p = 0.007). Δresistance values were associated with overt HE at six months (10 kHz [4.9 ± 2.5 vs -0.4 ± 4.7; p = 0.046]). Conclusions: in conclusion, a significant correlation between peripheral impedance and hemodynamic changes was found. Impedance was also significantly related to prognosis and overt hepatic encephalopathy

Definite and indeterminate nonalcoholic steatohepatitis share similar clinical features and prognosis: A longitudinal study of 1893 biopsy-proven nonalcoholic fatty liver disease subjects

Background and Aim: Histological score systems may not fully capture the essential nonalcoholic steatohepatitis (NASH) features, which is one of the leading causes of screening failure in clinical trials. We assessed the NASH distribution and its components across the fibrosis stages and their impact on the prognosis and their relationship with the concept of metabolic-associated fatty liver disease (MAFLD). Methods: Spanish multicenter study including 1893 biopsy-proven nonalcoholic fatty liver disease (NAFLD) patients from HEPAmet registry. NASH was diagnosed by NAS score ≥4 (including steatosis, ballooning and lobular inflammation) and fibrosis by Kleiner score. The presence of MAFLD was determined. Progression to cirrhosis, first episode of decompensated cirrhosis and death were collected during the follow-up (4.7 ± 3.8 years). Results: Fibrosis was F0 34.3% (649/1893), F1 27% (511/1893), F2 16.5% (312/1893), F3 15% (284/1893) and F4 7.2% (137/1893). NASH diagnosis 51.9% (982/1893), and its individual components (severe steatosis, ballooning and lobular inflammation), increased from F0 (33.6%) to F2 (68.6%), and decreased significantly in F4 patients (51.8%) (P = .0001). M ore t han 7 0% o f n on-NASH p atients s howed s ome i nflammatory activity (ballooning or lobular inflammation), showing a similar MAFLD rate than NASH (96.2% [945/982] vs. 95.2% [535/562]) and significantly higher than nonalcoholic fatty liver (NAFL) subjects (89.1% [311/349]) (P < .0001). Progression to cirrhosis was similar between NASH (9.5% [51/539]) and indeterminate NASH (7.9% [25/316]), and higher than steatosis (5% [14/263]) (logRank 8.417; P = .015). Death and decompensated cirrhosis were similar between these. Conclusions: The prevalence of steatohepatitis decreased in advanced liver disease. However, most of these patients showed some inflammatory activity histologically and had metabolic disturbances. These findings should be considered in clinical trials whose main aim is to prevent cirrhosis progression and complications, liver transplant and death

Usefulness of bioelectrical impedance analysis for monitoring patients with refractory ascites

Background: bioelectrical impedance analysis is a technique for the determination of the hydropic component. The hydropic component, determined by blood volume, could be a reflection of the hemodynamic situation. This study aimed to evaluate the usefulness of peripheral bioelectrical impedance analysis (BIA) for the prediction of hemodynamic changes in large-volume paracentesis and prognosis. Methods: this was a proof-of-concept prospective study of 14 patients with liver cirrhosis and refractory ascites. Peripheral bioimpedance was measured three times using a portable device, IVOL®, before and after large-volume paracentesis, at different frequencies (5, 10, 20, 50, 100 and 200 kHz). Consequently, resistance, reactance and phase angle were obtained, both pre- and post-paracentesis (the difference between them was defined as ¿). Results: the mean age of patients was 62.2 ± 9.6 years, the Child-Pugh was 8.4 ± 1.3 and the MELD score was 15.2 ± 3.9. A direct correlation between the extraction of ascitic fluid and ¿resistance (10 kHz [r = 0.722; n = 12; p = 0.008], 20 kHz [r = 0.658; n = 12; p = 0.020] and 50 kHz [r = 0.519; n = 14; p = 0.057]) was observed. The presence of edema was related to lower values of both pre-paracentesis resistance (10 Hz [23.9 ± 8 vs 32.2 ± 4; p = 0.043]) and phase angle (5 kHz [-1.9 ± 2.8 vs 5.9 ± 7.3; p = 0.032]). Pre-paracentesis phase angle was directly correlated with the decline in blood pressure after paracentesis at lower frequencies (5 kHz [r = 0.694; n = 13; p = 0.008] and 10 kHz [r = 0.661; n = 13; p = 0.014]). Lower frequencies of ¿phase-angle impacted on patient prognosis (5 kHz [-8.6 ± 5 vs -2.5 ± 2.7; p = 0.021]), patients with ¿phase-angle 5 kHz > -4 had a higher rate of mortality (83.3% [5/6] vs 0% [0/6]; logRank 7.306, p = 0.007). ¿resistance values were associated with overt HE at six months (10 kHz [4.9 ± 2.5 vs -0.4 ± 4.7; p = 0.046]). Conclusions: in conclusion, a significant correlation between peripheral impedance and hemodynamic changes was found. Impedance was also significantly related to prognosis and overt hepatic encephalopathy.Peer ReviewedPostprint (published version

Hepatobiliary manifestations in inflammatory bowel disease: The gut, the drugs and the liver

Abnormal liver biochemical tests are present in up to 30% of patients with inflammatory bowel disease (IBD), and therefore become a diagnostic challenge. Liver and biliary tract diseases are common extraintestinal manifestations for both Crohn’s disease and ulcerative colitis (UC), and typically do not correlate with intestinal activity. Primary sclerosing cholangitis (PSC) is the most common hepatobiliary manifestation of IBD, and is more prevalent in UC. Approximately 5% of patients with UC develop PSC, with the prevalence reaching up to 90%. Cholangiocarcinoma and colon cancer risks are increased in these patients. Less common disorders include autoimmune hepatitis/PSC overlap syndrome, IgG4-associated cholangiopathy, primary biliary cirrhosis, hepatic amyloidosis, granulomatous hepatitis, cholelithiasis, portal vein thrombosis, liver abscess, and non-alcoholic fatty liver disease. Hepatitis B reactivation during immunosuppressive therapy is a major concern, with screening and vaccination being recommended in serologically negative cases for patients with IBD. Reactivation prophylaxis with entecavir or tenofovir for 6 to 12 mo after the end of immunosuppressive therapy is mandatory in patients showing as hepatitis B surface antigen (HBsAg) positive, independently from viral load. HBsAg negative and anti-HBc positive patients, with or without anti-HBs, should be closely monitored, measuring alanine aminotransferase and hepatitis B virus DNA within 12 mo after the end of therapy, and should be treated if the viral load increases. On the other hand, immunosuppressive therapy does not seem to promote reactivation of hepatitis C, and hepatitis C antiviral treatment does not influence IBD natural history either. Most of the drugs used for IBD treatment may induce hepatotoxicity, although the incidence of serious adverse events is low. Abnormalities in liver biochemical tests associated with aminosalicylates are uncommon and are usually not clinically relevant. Methotrexate-related hepatotoxicity has been described in 14% of patients with IBD, in a dose-dependent manner. Liver biopsy is not routinely recommended. Biologics-related hepatotoxicity is rare, but has been shown most frequently in patients treated with infliximab. Thiopurines have been associated with veno-occlusive disease, regenerative nodular hyperplasia, and liver peliosis. Routine liver biochemical tests are recommended, especially during the first month of treatment. All these conditions should be considered in IBD patients with clinical or biochemical features suggestive of hepatobiliary involvement. Diagnosis and management of these disorders usually involve hepatologists and gastroenterologists due to its complexity

A Shortcut from Metabolic-Associated Fatty Liver Disease (MAFLD) to Hepatocellular Carcinoma (HCC): c-MYC a Promising Target for Preventative Strategies and Individualized Therapy

Background: Metabolic-associated fatty liver disease (MAFLD) has risen as one of the leading etiologies for hepatocellular carcinoma (HCC). Oncogenes have been suggested to be responsible for the high risk of MAFLD-related HCC. We analyzed the impact of the proto-oncogene c-MYC in the development of human and murine MAFLD and MAFLD-associated HCC. Methods: alb-myctg mice were studied at baseline conditions and after administration of Western diet (WD) in comparison to WT littermates. c-MYC expression was analyzed in biopsies of patients with MAFLD and MAFLD-associated HCC by immunohistochemistry. Results: Mild obesity, spontaneous hyperlipidaemia, glucose intolerance and insulin resistance were characteristic of 36-week-old alb-myctg mice. Middle-aged alb-myctg exhibited liver steatosis and increased triglyceride content. Liver injury and inflammation were associated with elevated ALT, an upregulation of ER-stress response and increased ROS production, collagen deposition and compensatory proliferation. At 52 weeks, 20% of transgenic mice developed HCC. WD feeding exacerbated metabolic abnormalities, steatohepatitis, fibrogenesis and tumor prevalence. Therapeutic use of metformin partly attenuated the spontaneous MAFLD phenotype of alb-myctg mice. Importantly, upregulation and nuclear localization of c-MYC were characteristic of patients with MAFLD and MAFLD-related HCC. Conclusions: A novel function of c-MYC in MAFLD progression was identified opening new avenues for preventative strategiesMINECO Retos SAF2016-78711SAF2017-87919-RPID2020-117827RB-IOOPID2020-117941RB-IOOPID2020-117116RB-I00EXOHEP-CM S2017/BMD- 3727NanoLiver-CM Y2018/NMT-4949AMMF 2018/117COST Action CA17112UCM-25/2019La Caixa Foundation Program HR17-00601Asociación Española Contra el Cáncer AECC PROYE20084 REGUthe German Research Foundation SFB1382 Project ID 403224013/A02Ramón y Cajal Researchers RYC-2014-15242RYC-2015-17438Instituto de Salud Carlos III PI16/01842, PI19/01404; PI19/00589The German Research Foundation SFB1382 Project ID 403224013/B0

Impact of COVID-19 on liver disease: From the experimental to the clinic perspective.

Coronavirus disease 2019 (COVID-19) has caused a global pandemic unprecedented in over a century. Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a predominantly respiratory infection, various degrees of liver function abnormalities have been reported. Pre-existing liver disease in patients with SARS-CoV-2 infection has not been comprehensively evaluated in most studies, but it can critically compromise survival and trigger hepatic decompensation. The collapse of the healthcare services has negatively impacted the diagnosis, monitoring, and treatment of liver diseases in non-COVID-19 patients. In this review, we aim to discuss the impact of COVID-19 on liver disease from the experimental to the clinic perspective. Gato S, Lucena-Valera A, Muñoz-Hernández R, Sousa JM, Romero-Gómez M, Ampuero J. Impact of COVID-19 on liver disease: From the experimental to the clinic perspective. World J Virol 2021; 10(6): 301-311 [PMID: 34909404 DOI: 10.5501/wjv.v10.i6.301

Clinical characteristics and outcome of drug-induced liver injury in the older patients: from the young-old to the oldest-old

Older patients with hepatotoxicity have been scarcely studied in idiosyncratic drug-induced liver injury (DILI) cohorts. We sought the distinctive characteristics of DILI in older patients across age groups. A total of 882 DILI patients included in the Spanish DILI Registry (33% ≥ 65 years) were categorized according to age: “young” (< 65 years); “young-old” (65–74 years); “middle-old” (75–84 years); and “oldest-old” (≥ 85 years). All elderly groups had an increasingly higher comorbidity burden (P < 0.001) and polypharmacy (P < 0.001). There was a relationship between jaundice and hospitalization (P < 0.001), and both were more prevalent in the older age groups, especially in the oldest-old (88% and 69%, respectively), and the DILI episode was more severe (P = 0.029). The proportion of females decreased across age groups from the young to the middle-old, yet in the oldest-old there was a distinct female predominance. Pattern of liver injury shifted towards cholestatic with increasing age among top culprit drugs amoxicillin-clavulanate, atorvastatin, levofloxacin, ibuprofen, and ticlopidine. The best cutoff point for increased odds of cholestatic DILI was 65 years. Older patients had increased non–liver-related mortality (P = 0.030) as shown by the predictive capacity of the Model for End-Stage Liver Disease score (odds ratio (OR) = 1.116; P < 0.001), and comorbidity burden (OR = 4.188; P = 0.001) in the 6-month mortality. Older patients with DILI exhibited an increasingly predominant cholestatic phenotype across a range of culprit drugs, other than amoxicillin-clavulanate, with increased non–liver-related mortality and require a different approach to predict outcome. The oldest DILI patients exhibited a particular phenotype with more severe DILI episodes and need to be considered when stratifying older DILI populations