RESUMEN
Several genetic discoveries robustly implicate five single-nucleotide variants in the progression of non-alcoholic fatty liver disease to non-alcoholic steatohepatitis and fibrosis (NASH-fibrosis), including a recently identified variant in MTARC1. To better understand these variants as potential therapeutic targets, we aimed to characterize their impact on metabolism using comprehensive metabolomics data from two population-based studies. A total of 9135 participants from the Fenland study and 9902 participants from the EPIC-Norfolk cohort were included in the study. We identified individuals with risk alleles associated with NASH-fibrosis: rs738409C>G in PNPLA3, rs58542926C>T in TM6SF2, rs641738C>T near MBOAT7, rs72613567TA>T in HSD17B13 and rs2642438A>G in MTARC1. Circulating levels of 1449 metabolites were measured using targeted and untargeted metabolomics. Associations between NASH-fibrosis variants and metabolites were assessed using linear regression. The specificity of variant-metabolite associations were compared to metabolite associations with ultrasound-defined steatosis, gene variants linked to liver fat (in GCKR, PPP1R3B and LYPLAL1) and gene variants linked to cirrhosis (in HFE and SERPINA1). Each NASH-fibrosis variant demonstrated a specific metabolite profile with little overlap (8/97 metabolites) comprising diverse aspects of lipid metabolism. Risk alleles in PNPLA3 and HSD17B13 were both associated with higher 3-methylglutarylcarnitine and three variants were associated with lower lysophosphatidylcholine C14:0. The risk allele in MTARC1 was associated with higher levels of sphingomyelins. There was no overlap with metabolites that associated with HFE or SERPINA1 variants. Our results suggest a link between the NASH-protective variant in MTARC1 to the metabolism of sphingomyelins and identify distinct molecular patterns associated with each of the NASH-fibrosis variants under investigation.
Asunto(s)
Predisposición Genética a la Enfermedad , Cirrosis Hepática/patología , Metaboloma , Enfermedad del Hígado Graso no Alcohólico/patología , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Femenino , Estudios de Asociación Genética , Humanos , Cirrosis Hepática/complicaciones , Cirrosis Hepática/genética , Cirrosis Hepática/metabolismo , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Pronóstico , Estudios ProspectivosRESUMEN
AIMS: Liver pathology is a challenging subspeciality, with histopathologists frequently seeking specialist opinions. This study aims to determine the impact of specialist reviews on the final diagnosis and patient management. METHODS AND RESULTS: Agreement with the initial reporting centre in the histopathological diagnosis of 1265 liver biopsies was determined. The nature of differences was explored in more depth for 103 discrepant cases. Differences in the histopathological interpretation were present in 749 of 1265 (59%) biopsies, of which 505 of 749 (67%) were predicted at the time of reporting to impact upon patient management. Agreement was good in cases with chronic viral hepatitis, fatty liver disease, malignancy and minimal pathological changes, while diagnostic differences occurred in more than 70% with biliary disease, autoimmune hepatitis or vascular/architectural changes. A clinical review of a subset of reports with histopathological differences predicted changes in patient management in 63 of 103 (61%). CONCLUSIONS: Clinically significant differences in liver biopsy interpretation between local pathologists and subspecialists are common. Diagnoses with frequent discrepancies, such as biliary disease, may benefit from a specialist review as standard when diagnosed initially, while cases requiring specialist advice from disease subgroups where discrepancies are less common, such as chronic viral hepatitis, could be selected during the clinicopathological conference process.
Asunto(s)
Hígado Graso/diagnóstico , Hepatitis Autoinmune/diagnóstico , Hepatopatías/diagnóstico , Hígado/patología , Derivación y Consulta/normas , Biopsia , Errores Diagnósticos/prevención & control , Hígado Graso/patología , Hepatitis Autoinmune/patología , Humanos , Hepatopatías/patología , EspecializaciónRESUMEN
Ischemia/reperfusion injury (IRI) that develops after liver implantation may prejudice long-term graft survival, but it remains poorly understood. Here we correlate the severity of IRIs that were determined by histological grading of time-zero biopsies sampled after graft revascularization with patient and graft outcomes. Time-zero biopsies of 476 liver transplants performed at our center between 2000 and 2010 were graded as follows: nil (10.5%), mild (58.8%), moderate (26.1%), and severe (4.6%). Severe IRI was associated with donor age, donation after circulatory death, prolonged cold ischemia time, and liver steatosis, but it was also associated with increased rates of primary nonfunction (9.1%) and retransplantation within 90 days (22.7%). Longer term outcomes in the severe IRI group were also poor, with 1-year graft and patient survival rates of only 55% and 68%, respectively (cf. 90% and 93% for the remainder). Severe IRI on the time-zero biopsy was, in a multivariate analysis, an independent determinant of 1-year graft survival and was a better predictor of 1-year graft loss than liver steatosis, early graft dysfunction syndrome, and high first-week alanine aminotransferase with a positive predictive value of 45%. Time-zero biopsies predict adverse clinical outcomes after liver transplantation, and severe IRI upon biopsy signals the likely need for early retransplantation.
Asunto(s)
Trasplante de Hígado/efectos adversos , Daño por Reperfusión/patología , Adulto , Factores de Edad , Anciano , Alanina Transaminasa/sangre , Aloinjertos , Biomarcadores/sangre , Biopsia , Isquemia Fría/efectos adversos , Femenino , Supervivencia de Injerto , Humanos , Estimación de Kaplan-Meier , Trasplante de Hígado/mortalidad , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Daño por Reperfusión/sangre , Daño por Reperfusión/etiología , Daño por Reperfusión/mortalidad , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Factores de Tiempo , Donantes de Tejidos , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: The term 'zero tolerance' has recently been applied to healthcare-associated infections, implying that such events are always preventable. This may not be the case for healthcare-associated infections such as methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia. METHODS: We combined information from an epidemiological investigation and bacterial whole-genome sequencing to evaluate a cluster of five MRSA bacteraemia episodes in four patients in a specialist hepatology unit. RESULTS: The five MRSA bacteraemia isolates were highly related by multilocus sequence type (ST) (four isolates were ST22 and one isolate was a single-locus variant, ST2046). Whole-genome sequencing demonstrated unequivocally that the bacteraemia cases were unrelated. Placing the MRSA bacteraemia isolates within a local and global phylogenetic tree of MRSA ST22 genomes demonstrated that the five bacteraemia isolates were highly diverse. This was consistent with the acquisition and importation of MRSA from the wider referral network. Analysis of MRSA carriage and disease in patients within the hepatology service demonstrated a higher risk of both initial MRSA acquisition compared with the nephrology service and a higher risk of progression from MRSA carriage to bacteraemia, compared with patients in nephrology or geriatric services. A root cause analysis failed to reveal any mechanism by which three of five MRSA bacteraemia episodes could have been prevented. CONCLUSIONS: This study illustrates the complex nature of MRSA carriage and bacteraemia in patients in a specialized hepatology unit. Despite numerous ongoing interventions to prevent MRSA bacteraemia in healthcare settings, these are unlikely to result in a zero incidence in referral centres that treat highly complex patients.
Asunto(s)
Bacteriemia/mortalidad , Infección Hospitalaria/prevención & control , Atención a la Salud/normas , Infecciones Estafilocócicas/prevención & control , Infecciones Estafilocócicas/transmisión , Antibacterianos/farmacología , Bacteriemia/microbiología , Bacteriemia/prevención & control , Técnicas de Tipificación Bacteriana , Secuencia de Bases , Infección Hospitalaria/microbiología , ADN Bacteriano/genética , Brotes de Enfermedades , Enfermedad Hepática en Estado Terminal/microbiología , Humanos , Resistencia a la Meticilina , Staphylococcus aureus Resistente a Meticilina/genética , Staphylococcus aureus Resistente a Meticilina/aislamiento & purificación , Pruebas de Sensibilidad Microbiana , Tipificación de Secuencias Multilocus , Filogenia , Análisis de Secuencia de ADN , Infecciones Estafilocócicas/microbiologíaRESUMEN
BACKGROUND: Bile chemistry during normothermic ex situ liver perfusion (NESLiP) has been suggested to be an indicator of cholangiopathy. The normal range of biochemical variables in bile of livers undergoing NESLiP has not been defined, nor have published biliary viability criteria been assessed against instances of posttransplant nonanastomotic bile strictures (NASs). METHODS: The bile and perfusate chemistry of 200 livers undergoing NESLiP between February 1, 2018, and October 30, 2023, was compared. In addition, 11 livers that underwent NESLiP and later developed NAS were selected and their bile chemistry was also examined. RESULTS: In livers that did not develop cholangiopathy, concentrations of sodium, potassium, and chloride were slightly higher in bile than in perfusate, whereas the concentration of calcium was slightly lower. Bile was alkali and had a lower glucose concentration than perfusate. Cholangiocyte glucose reabsorption was shown to saturate at high perfusate concentrations and was more impaired in livers donated after circulatory death than in livers donated after brain death. Published criteria failed to identify all livers that went on to develop NASs. CONCLUSIONS: A significant false-negative rate exists with current biliary viability criteria, probably reflecting the patchy and incomplete nature of the development of NASs in the biliary tree. The data presented here provide a benchmark for future assessment of bile duct chemistry during NESLiP.
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Bilis , Trasplante de Hígado , Hígado , Preservación de Órganos , Perfusión , Humanos , Trasplante de Hígado/efectos adversos , Bilis/metabolismo , Bilis/química , Preservación de Órganos/métodos , Hígado/metabolismo , Masculino , Femenino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Colestasis , Adulto , Estudios Retrospectivos , Constricción PatológicaRESUMEN
OBJECTIVES: Conventional imaging techniques are insensitive to liver fibrosis. This study assesses the diagnostic accuracy of MR elastography (MRE) stiffness values and the ratio of phosphomonoesters (PME)/phosphodiesters (PDE) measured using (31)P spectroscopy against histological fibrosis staging. METHODS: The local research ethics committee approved this prospective, blinded study. A total of 77 consecutive patients (55 male, aged 49 ± 11.5 years) with a clinical suspicion of liver fibrosis underwent an MR examination with a liver biopsy later the same day. Patients underwent MRE and (31)P spectroscopy on a 1.5 T whole body system. The liver biopsies were staged using an Ishak score for chronic hepatitis or a modified NAS fibrosis score for fatty liver disease. RESULTS: MRE increased with and was positively associated with fibrosis stage (Spearman's rank = 0.622, P < 0.001). PME/PDE was not associated with fibrosis stage (Spearman's rank = -0.041, p = 0.741). Area under receiver operating curves for MRE stiffness values were high (range 0.75-0.97). The diagnostic utility of PME/PDE was no better than chance (range 0.44-0.58). CONCLUSIONS: MRE-estimated liver stiffness increases with fibrosis stage and is able to dichotomise fibrosis stage groupings. We did not find a relationship between (31)P MR spectroscopy and fibrosis stage. KEY POINTS: Magnetic resonance elastography (MRE) and MR spectroscopy can both assess the liver. MRE is superior to ( 31 ) P MR spectroscopy in staging hepatic fibrosis. MRE is able to dichotomise liver fibrosis stage groupings. Gradient-echo MRE may be problematic in genetic haemochromatosis.
Asunto(s)
Diagnóstico por Imagen de Elasticidad/métodos , Cirrosis Hepática/patología , Espectroscopía de Resonancia Magnética/métodos , Biopsia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Curva ROCRESUMEN
OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) is a silent pandemic associated with obesity and the metabolic syndrome, and also increases cardiovascular- and cirrhosis-related morbidity and mortality. A complete understanding of adaptive compensatory metabolic programmes that modulate non-alcoholic steatohepatitis (NASH) progression is lacking. METHODS AND RESULTS: Transcriptomic analysis of liver biopsies in patients with NASH revealed that NASH progression is associated with rewiring of metabolic pathways, including upregulation of de novo lipid/cholesterol synthesis and fatty acid remodelling. The modulation of these metabolic programmes was achieved by activating sterol regulatory element-binding protein (SREBP) transcriptional networks; however, it is still debated whether, in the context of NASH, activation of SREBPs acts as a pathogenic driver of lipotoxicity, or rather promotes the biosynthesis of protective lipids that buffer excessive lipid accumulation, preventing inflammation and fibrosis. To elucidate the pathophysiological role of SCAP/SREBP in NASH and wound-healing response, we used an Insig1 deficient (with hyper-efficient SREBPs) murine model challenged with a NASH-inducing diet. Despite enhanced lipid and cholesterol biosynthesis, Insig1 KO mice had similar systemic metabolism and insulin sensitivity to Het/WT littermates. Moreover, activating SREBPs resulted in remodelling the lipidome, decreased hepatocellular damage, and improved wound-healing responses. CONCLUSIONS: Our study provides actionable knowledge about the pathways and mechanisms involved in NAFLD pathogenesis, which may prove useful for developing new therapeutic strategies. Our results also suggest that the SCAP/SREBP/INSIG1 trio governs transcriptional programmes aimed at protecting the liver from lipotoxic insults in NASH.
Asunto(s)
Colesterol/biosíntesis , Progresión de la Enfermedad , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Lipogénesis/genética , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Animales , Biomarcadores/metabolismo , Dieta Occidental , Femenino , Humanos , Resistencia a la Insulina/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Cirrosis Hepática/genética , Cirrosis Hepática/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/genética , TranscriptomaRESUMEN
The prevalence of nonalcoholic steatohepatitis (NASH) and liver cancer is increasing. De novo lipogenesis and fibrosis contribute to disease progression and cancerous transformation. Here, we found that ß2-spectrin (SPTBN1) promotes sterol regulatory element (SRE)binding protein (SREBP)stimulated lipogenesis and development of liver cancer in mice fed a high-fat diet (HFD) or a western diet (WD). Either hepatocyte-specific knockout of SPTBN1 or siRNA-mediated therapy protected mice from HFD/WD-induced obesity and fibrosis, lipid accumulation, and tissue damage in the liver. Biochemical analysis suggested that HFD/WD induces SPTBN1 and SREBP1 cleavage by CASPASE-3 and that the cleaved products interact to promote expression of genes with sterol response elements. Analysis of human NASH tissue revealed increased SPTBN1 and CASPASE-3 expression. Thus, our data indicate that SPTBN1 represents a potential target for therapeutic intervention in NASH and liver cancer.
Asunto(s)
Neoplasias , Enfermedad del Hígado Graso no Alcohólico , Animales , Dieta Alta en Grasa/efectos adversos , Hígado/metabolismo , Ratones , Ratones Endogámicos C57BL , Neoplasias/metabolismo , Enfermedad del Hígado Graso no Alcohólico/genética , Espectrina/metabolismoRESUMEN
Methionine-1 (M1)-linked polyubiquitin chains conjugated by the linear ubiquitin chain assembly complex (LUBAC) control NF-κB activation, immune homoeostasis, and prevents tumour necrosis factor (TNF)-induced cell death. The deubiquitinase OTULIN negatively regulates M1-linked polyubiquitin signalling by removing the chains conjugated by LUBAC, and OTULIN deficiency causes OTULIN-related autoinflammatory syndrome (ORAS) in humans. However, the cellular pathways and physiological functions controlled by OTULIN remain poorly understood. Here, we show that OTULIN prevents development of liver disease in mice and humans. In an ORAS patient, OTULIN deficiency caused spontaneous and progressive steatotic liver disease at 10-13 months of age. Similarly, liver-specific deletion of OTULIN in mice leads to neonatally onset steatosis and hepatitis, akin to the ORAS patient. OTULIN deficiency triggers metabolic alterations, apoptosis, and inflammation in the liver. In mice, steatosis progresses to steatohepatitis, fibrosis and pre-malignant tumour formation by 8 weeks of age, and by the age of 7-12 months the phenotype has advanced to malignant hepatocellular carcinoma. Surprisingly, the pathology in OTULIN-deficient livers is independent of TNFR1 signalling. Instead, we find that steatohepatitis in OTULIN-deficient livers is associated with aberrant mTOR activation, and inhibition of mTOR by rapamycin administration significantly reduces the liver pathology. Collectively, our results reveal that OTULIN is critical for maintaining liver homoeostasis and suggest that M1-linked polyubiquitin chains may play a role in regulation of mTOR signalling and metabolism in the liver.
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Endopeptidasas/metabolismo , Inflamación/complicaciones , Cirrosis Hepática/complicaciones , Neoplasias Hepáticas/complicaciones , Hígado/patología , Animales , Animales Recién Nacidos , Carcinogénesis/metabolismo , Carcinogénesis/patología , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Muerte Celular , Proliferación Celular , Endopeptidasas/deficiencia , Hígado Graso/complicaciones , Femenino , Eliminación de Gen , Hematopoyesis , Humanos , Inflamación/patología , Hígado/efectos de los fármacos , Cirrosis Hepática/patología , Neoplasias Hepáticas/patología , Masculino , Ratones , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Transducción de Señal , Sirolimus , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Non-alcoholic steatohepatitis (NASH) is characterized by lipotoxicity, inflammation and fibrosis, ultimately leading to end-stage liver disease. The molecular mechanisms promoting NASH are poorly understood, and treatment options are limited. Here, we demonstrate that hepatic expression of bone morphogenetic protein 8B (BMP8B), a member of the transforming growth factor beta (TGFß)-BMP superfamily, increases proportionally to disease stage in people and animal models with NASH. BMP8B signals via both SMAD2/3 and SMAD1/5/9 branches of the TGFß-BMP pathway in hepatic stellate cells (HSCs), promoting their proinflammatory phenotype. In vivo, the absence of BMP8B prevents HSC activation, reduces inflammation and affects the wound-healing responses, thereby limiting NASH progression. Evidence is featured in primary human 3D microtissues modelling NASH, when challenged with recombinant BMP8. Our data show that BMP8B is a major contributor to NASH progression. Owing to the near absence of BMP8B in healthy livers, inhibition of BMP8B may represent a promising new therapeutic avenue for NASH treatment.
Asunto(s)
Proteínas Morfogenéticas Óseas/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Animales , Proteínas Morfogenéticas Óseas/genética , Intoxicación por Tetracloruro de Carbono/metabolismo , Dieta Alta en Grasa , Dieta Occidental , Células Estrelladas Hepáticas/metabolismo , Humanos , Inflamación/genética , Regeneración Hepática/efectos de los fármacos , Regeneración Hepática/genética , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/genética , Proteínas Recombinantes/farmacología , Proteínas Smad/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Cicatrización de Heridas/genéticaRESUMEN
Fatty liver is increasingly becoming more problematic from a clinical perspective. This article describes fatty liver and its clinical presentation. The current understanding of processes underlying fatty liver is reviewed, as well as the evidence for therapeutic options.
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Hígado Graso , Biopsia/métodos , Hígado Graso/etiología , Hígado Graso/patología , Hígado Graso/terapia , Hepatomegalia/etiología , Humanos , Hígado/enzimología , Hígado/patología , Pruebas de Función Hepática , Factores de Riesgo , Esplenomegalia/etiologíaRESUMEN
Non-alcoholic fatty liver disease (NAFLD) is an increasingly common condition, strongly associated with the metabolic syndrome, that can lead to progressive hepatic fibrosis, cirrhosis and hepatic failure. Subtle inter-patient genetic variation and environmental factors combine to determine variation in disease progression. A common non-synonymous polymorphism in TM6SF2 (rs58542926 c.449 C>T, p.Glu167Lys) was recently associated with increased hepatic triglyceride content, but whether this variant promotes clinically relevant hepatic fibrosis is unknown. Here we confirm that TM6SF2 minor allele carriage is associated with NAFLD and is causally related to a previously reported chromosome 19 GWAS signal that was ascribed to the gene NCAN. Furthermore, using two histologically characterized cohorts encompassing steatosis, steatohepatitis, fibrosis and cirrhosis (combined n=1,074), we demonstrate a new association, independent of potential confounding factors (age, BMI, type 2 diabetes mellitus and PNPLA3 rs738409 genotype), with advanced hepatic fibrosis/cirrhosis. These findings establish new and important clinical relevance to TM6SF2 in NAFLD.
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Cirrosis Hepática/genética , Proteínas de la Membrana/genética , Enfermedad del Hígado Graso no Alcohólico/genética , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Alelos , Proteoglicanos Tipo Condroitín Sulfato/genética , Proteoglicanos Tipo Condroitín Sulfato/metabolismo , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Heterocigoto , Humanos , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Hígado/metabolismo , Hígado/patología , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Masculino , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neurocano , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patologíaRESUMEN
Renal impairment is common in patients after liver transplantation and is attributable in large part to the use of calcineurin inhibitor (CNI)-based immunosuppression. We sought to determine whether conversion to sirolimus-based immunosuppression was associated with improved renal function. In a single-center, randomized, controlled trial, 30 patients at least 6 months post liver transplantation were randomized to remain on CNI-based immunosuppression or to switch to sirolimus-based immunosuppression. The primary outcome measure was change in measured glomerular filtration rate (GFR) between baseline and 12 months. Of 30 patients randomized, 3 were withdrawn at randomization, leaving 14 patients on CNI and 13 on sirolimus. There was a significant improvement in delta GFR following conversion to sirolimus at 3 months (7.7 mL/minute/1.73 m2; 95% confidence interval, 3.5-11.9) and 1 yr (6.1 mL/minute/1.73 m2; 95% confidence interval, 0.9-11.4). The difference in absolute GFR between the 2 study groups was significant at 3 months (P=0.02), but not at 12 months (P=0.07). The principal adverse events following conversion were the development of skin rash (9 of 13 patients, 69%) and mouth ulcers (5 of 13 patients, 38%). Two patients developed acute rejection at 2 and 3 months following conversion, 1 in association with low sirolimus levels and 1 having stopped the drug inadvertently. In conclusion, overall, this study suggests that conversion to sirolimus immunosuppression is associated with a modest improvement in renal function. Side effects were common, but tolerable in most patients and controlled with dose reduction.
Asunto(s)
Inhibidores de la Calcineurina , Ciclosporina/efectos adversos , Rechazo de Injerto/prevención & control , Inmunosupresores/efectos adversos , Enfermedades Renales/inducido químicamente , Trasplante de Hígado , Sirolimus/efectos adversos , Tacrolimus/efectos adversos , Presión Sanguínea/efectos de los fármacos , Quimioterapia Combinada , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Humanos , Enfermedades Renales/sangre , Enfermedades Renales/fisiopatología , Masculino , Persona de Mediana Edad , Calidad de Vida , Factores de Tiempo , Resultado del TratamientoRESUMEN
Sirolimus-induced pneumonitis has emerged as a potentially serious complication in renal transplantation but only single case reports of this condition have been described after liver transplantation (LT), where experience with sirolimus is relatively limited. We report our experience, the largest to date, of sirolimus-induced pneumonitis following LT. Between 1999 and 2006, 186 liver transplant patients received sirolimus-based immunosuppression, after initial therapy with calcineurin inhibitors (CNIs). All cases of sirolimus-induced pneumonitis were recorded and a retrospective review of the case notes of such patients was undertaken for the purpose of this analysis. Of 186 liver transplant patients receiving sirolimus, 4 (2.2%) developed pneumonitis that was attributed to the drug; the time from starting sirolimus to presentation was varied (1.5-30 months). The most common presenting symptoms were dyspnea, cough and fatigue. The median sirolimus level at the time of diagnosis was 9.7 ng/mL (range, 7-19.5 ng/mL). All patients in the series underwent thoracic computed tomography, which showed similar changes in all patients, and lung biopsy, which revealed features consistent with a drug-induced pneumonitis. In all 4 patients, sirolimus-induced pneumonitis resolved following cessation of therapy but took weeks to months for complete recovery. In conclusion, sirolimus-induced pneumonitis occurred in at least 2% of liver transplant recipients and should be suspected in patients who develop respiratory symptoms while on sirolimus. Although it may be life threatening, early recognition and cessation of sirolimus can lead to complete resolution of pneumonitis.