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Acute severe hepatitis associated with active human herpesvirus 6 (HHV-6) infection is a rare life-threatening condition with unclear clinical course and histopathology. In this study, we retrospectively analyzed 5 patients with indeterminate acute severe hepatitis found to have active hepatic HHV-6 infection during care. All patients were previously healthy children presenting with a nonspecific prodrome. Four developed acute liver failure (ALF) and 3 received liver transplantation. The explanted livers and biopsies demonstrated a centrilobular pattern of necroinflammation characterized by moderate to marked central perivenulitis and confluent centrilobular to panlobular necrosis in 4 cases, accompanied by marked hepatocellular swelling and milder portal inflammation in 3. Central perivenulitis was more prominent in comparison to a control of group of ALF without HHV-6 ( P =0.01). When compared with the children with acute severe hepatitis associated with adenovirus encountered in the recent outbreak, both central perivenulitis and centrilobular necrosis were significant predictors for association with HHV-6 ( P <0.01). Liver immunohistochemistry detected HHV-6 structural protein in biliary epithelium in all cases and a predominance of CD8 + T cells in the perivenular inflammatory infiltrate. Among the 4 patients with ALF, one received early anti-HHV-6 therapy and had transplant-free survival, while the other 3 received either general prophylactic antiviral treatment only (n=2) or late anti-HHV-6 therapy (n=1) and needed liver transplantation. Our findings were similar to those in previously reported cases. In summary, acute severe hepatitis associated with HHV-6 tends to affect children, progress to ALF, and exhibit characteristic centrilobular necroinflammation which likely represents an immune-mediated process.
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Herpesvirus Humano 6 , Trasplante de Hígado , Infecciones por Roseolovirus , Humanos , Herpesvirus Humano 6/aislamiento & purificación , Masculino , Estudios Retrospectivos , Infecciones por Roseolovirus/patología , Infecciones por Roseolovirus/virología , Infecciones por Roseolovirus/complicaciones , Femenino , Preescolar , Niño , Lactante , Enfermedad Aguda , Hepatitis Viral Humana/patología , Hepatitis Viral Humana/virología , Fallo Hepático Agudo/virología , Fallo Hepático Agudo/patología , Índice de Severidad de la Enfermedad , Hígado/patología , Hígado/virología , Inmunohistoquímica , Biopsia , AdolescenteRESUMEN
BACKGROUND: The molecular mechanisms underlying Fontan-associated liver disease (FALD) remain largely unknown. OBJECTIVES: This study aimed to assess intrahepatic transcriptomic differences among patients with FALD according to the degree of liver fibrosis and clinical outcomes. METHODS: This retrospective cohort study included adults with the Fontan circulation. Baseline clinical, laboratory, imaging, and hemodynamic data as well as a composite clinical outcome (CCO) were extracted from medical records. Patients were classified into early or advanced fibrosis. RNA was isolated from formalin-fixed paraffin-embedded liver biopsy samples; RNA libraries were constructed with the use of an rRNA depletion method and sequenced on an Illumina Novaseq 6000. Differential gene expression and gene ontology analyses were performed with the use of DESeq2 and Metascape. RESULTS: A total of 106 patients (48% male, median age 31 years [IQR: 11.3 years]) were included. Those with advanced fibrosis had higher B-type natriuretic peptide levels and Fontan, mean pulmonary artery, and capillary wedge pressures. The CCO was present in 23 patients (22%) and was not predicted by advanced liver fibrosis, right ventricular morphology, presence of aortopulmonary collaterals, or Fontan pressures on multivariable analysis. Samples with advanced fibrosis had 228 upregulated genes compared with early fibrosis. Samples with the CCO had 894 upregulated genes compared with those without the CCO. A total of 136 upregulated genes were identified in both comparisons and were enriched in cellular response to cytokine stimulus or oxidative stress, VEGFA-VEGFR2 signaling pathway, TGF-ß signaling pathway, and vasculature development. CONCLUSIONS: Patients with FALD and advanced fibrosis or the CCO exhibited upregulated genes related to inflammation, congestion, and angiogenesis.
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Procedimiento de Fontan , Cardiopatías Congénitas , Hepatopatías , Adulto , Humanos , Masculino , Femenino , Estudios Retrospectivos , Cirrosis Hepática/genética , Cirrosis Hepática/patología , Hepatopatías/genética , Hepatopatías/cirugía , Fibrosis , Perfilación de la Expresión Génica , ARN , Cardiopatías Congénitas/genética , Cardiopatías Congénitas/cirugíaRESUMEN
BACKGROUND: Ischemia-reperfusion injury (IRI) is a significant clinical concern in liver transplantation, with a key influence on short-term and long-term allograft and patient survival. Myeloid cells trigger and sustain tissue inflammation and damage associated with IRI, but the mechanisms regulating these activities are unknown. To address this, we investigated the molecular characteristics of intragraft myeloid cells present in biopsy-proven IRI- and IRI+ liver transplants. METHODS: RNA-sequencing was performed on 80 pre-reperfusion and post-reperfusion biopsies from 40 human recipients of liver transplantation (23 IRI+, 17 IRI-). We used transcriptional profiling and computational approaches to identify specific gene coexpression network modules correlated with functional subsets of MPO+, lysozyme+, and CD68+ myeloid cells quantified by immunohistochemistry on sequential sections from the same patient biopsies. RESULTS: A global molecular map showed gene signatures related to myeloid activation in all patients regardless of IRI status; however, myeloid cell subsets differed dramatically in their spatial morphology and associated gene signatures. IRI- recipients were found to have a natural corticosteroid production and response profile from pre-reperfusion to post-reperfusion, particularly among monocytes/macrophages. The pre-reperfusion signature of IRI+ recipients included acute inflammatory responses in neutrophils and increased translation of adaptive immune-related genes in monocytes/macrophages coupled with decreased glucocorticoid responses. Subsequent lymphocyte activation at post-reperfusion identified transcriptional programs associated with the transition to adaptive immunity found only among IRI+ recipients. CONCLUSIONS: Myeloid subset-specific genes and related signaling pathways provide targets for the development of therapeutic strategies aimed at limiting IRI in the clinical setting of liver transplantation.
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Trasplante de Hígado , Daño por Reperfusión , Humanos , Trasplante de Hígado/efectos adversos , Daño por Reperfusión/genética , Leucocitos , Inmunidad Adaptativa , Biopsia , InflamaciónRESUMEN
Validated nonbiopsy methods to assure duodenal mucosal healing in celiac disease are lacking, yet ongoing mucosal injury is associated with anemia, osteoporosis, and lymphoma. Most providers utilize clinical data as surrogates of mucosal status to avoid additional esophagogastroduodenoscopy. The reliability of such surrogates to predict mucosal recovery has been incompletely evaluated. The aim of this study was to rigorously assess patterns of histologic mucosal recovery at follow-up in celiac disease and to correlate findings with clinical data. Gastrointestinal pathologists from 13 centers evaluated initial and follow-up duodenal biopsies from 181 celiac disease patients. Marsh scores and intraepithelial lymphocytes (IELs)/100 enterocytes were assessed blindly. Histology at follow-up was correlated with symptoms, immunoglobulin A anti-tissue transglutaminase titers and gluten-free diet adherence. Fifty-six/181 (31%) patients had persistent villous blunting and 46/181 (25%) patients had just persistently elevated IELs at follow-up, with only 79/181 (44%) patients having complete histologic remission. IEL normalization (82/181; 45%) lagged villous recovery (125/181;69%). In a minority of patients, villous blunting was limited to proximal duodenal biopsies. No correlation was found between Marsh scores and symptoms, normalization of immunoglobulin A anti-tissue transglutaminase serology, or diet adherence. Children showed greater recovery of Marsh score ( P <0.001) and IELs ( P <0.01) than adults. Persistent mucosal injury is common in celiac disease, with discordant villous/IEL normalization. Pathologist awareness of expected findings in celiac disease follow-up biopsies, including their frequent lack of correlation with clinical data, is important for patient management, and has implications for eligibility criteria for therapeutics currently in development.
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Enfermedad Celíaca , Adulto , Niño , Humanos , Estudios de Seguimiento , Reproducibilidad de los Resultados , Duodeno/patología , Biopsia , Mucosa Intestinal/patología , Inmunoglobulina ARESUMEN
Background: Nonalcoholic steatohepatitis (NASH) is a severe immune-mediated stage of nonalcoholic fatty liver disease that is rapidly becoming the most common etiology requiring liver transplantation (LT), with Hispanics bearing a disproportionate burden. This study aimed to uncover the underlying immune mechanisms of the disparities experienced by Hispanic patients undergoing LT for NASH. Methods: We enrolled 164 LT recipients in our institutional review board-approved study, 33 of whom presented with NASH as the primary etiology of LT (20%), with 16 self-reported as Hispanic (48%). We investigated the histopathology of prereperfusion and postreperfusion biopsies, clinical liver function tests, longitudinal soluble cytokines via 38-plex Luminex, and immune cell phenotypes generated by prereperfusion and postreperfusion blood using 14-color flow cytometry and enzyme-linked immunosorbent assay. Results: Hispanic LT recipients transplanted for NASH were disproportionately female (81%) and disproportionately suffered poor outcomes in the first year posttransplant, including rejection (26%) and death (38%). Clinically, we observed increased pro-inflammatory and apoptotic histopathological features in biopsies, increased AST/international normalized ratio early posttransplantation, and a higher incidence of presensitization to mismatched HLA antigens expressed by the donor allograft. Experimental investigations revealed that blood from female Hispanic NASH patients showed significantly increased levels of leukocyte-attracting chemokines, innate-to-adaptive switching cytokines and growth factors, HMGB1 release, and TLR4/TLR8/TLR9/NOD1 activation, and produced a pro-inflammatory, pro-apoptotic macrophage phenotype with reduced CD14/CD68/CD66a/TIM-3 and increased CD16/CD11b/HLA-DR/CD80. Conclusions: A personalized approach to reducing immunological risk factors is urgently needed for this endotype in Hispanics with NASH requiring LT, particularly in females.
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Ischemia-reperfusion injury (IRI) during orthotopic liver transplantation (OLT) contributes to graft rejection and poor clinical outcomes. The disulfide form of high mobility group box 1 (diS-HMGB1), an intracellular protein released during OLT-IRI, induces pro-inflammatory macrophages. How diS-HMGB1 differentiates human monocytes into macrophages capable of activating adaptive immunity remains unknown. We investigated if diS-HMGB1 binds toll-like receptor (TLR) 4 and TLR9 to differentiate monocytes into pro-inflammatory macrophages that activate adaptive immunity and promote graft injury and dysfunction. Assessment of 106 clinical liver tissue and longitudinal blood samples revealed that OLT recipients were more likely to experience IRI and graft dysfunction with increased diS-HMGB1 released during reperfusion. Increased diS-HMGB1 concentration also correlated with TLR4/TLR9 activation, polarization of monocytes into pro-inflammatory macrophages, and production of anti-donor antibodies. In vitro, healthy volunteer monocytes stimulated with purified diS-HMGB1 had increased inflammatory cytokine secretion, antigen presentation machinery, and reactive oxygen species production. TLR4 inhibition primarily impeded cytokine/chemokine and costimulatory molecule programs, whereas TLR9 inhibition decreased HLA-DR and reactive oxygen species production. diS-HMGB1-polarized macrophages also showed increased capacity to present antigens and activate T memory cells. In murine OLT, diS-HMGB1 treatment potentiated ischemia-reperfusion-mediated hepatocellular injury, accompanied by increased serum alanine transaminase levels. This translational study identifies the diS-HMGB1/TLR4/TLR9 axis as potential therapeutic targets in OLT-IRI recipients.
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Proteína HMGB1 , Trasplante de Hígado , Daño por Reperfusión , Humanos , Ratones , Animales , Receptor Toll-Like 9/metabolismo , Proteína HMGB1/metabolismo , Receptor Toll-Like 4/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Hígado , Daño por Reperfusión/metabolismo , Macrófagos , Citocinas/metabolismo , Apoptosis , Ratones Endogámicos C57BLRESUMEN
Objectives: To correlate preoperative imaging of fecaliths with what is seen in surgical specimens. Background: Early studies considered radiological findings of appendicoliths as a contraindication for nonoperative treatment of appendicitis. There is no standard definition for what is labeled as an appendicolith radiologically and little is known about the pathological correlates of these lesions. Methods: A single center, retrospective study of a consecutive series of adult patients who underwent appendectomy for acute appendicitis from March 2021 to February 2022 was performed. The primary outcome was concordance between preoperative cross-sectional imaging description of appendicolith with postoperative gross pathology description. Images were retrospectively reviewed by an independent radiologist, and the presence and characteristics of appendicoliths and appendices were examined. Results: Of 88 cases of appendicitis, 86 were diagnosed preoperatively by computed tomography (CT) imaging. Appendicoliths were seen either on CT or pathology in 45 (51%) patients. Of these 45 patients, a total of 38 (84%) were identified radiographically, and 28 (62%) were identified on pathology. Of the 38 appendicoliths diagnosed on preoperative imaging, only 21 (55%) were confirmed pathologically. Additionally, of the 28 appendicoliths observed on pathology, only 21 (75%) were identified preoperatively on imaging. There was no appendiceal obstruction in 10 of the 40 cases (25%) in which retrospective radiological review identified appendicoliths. Conclusions: Discrepancies were observed between CT and pathology findings of appendicoliths. Not all appendicoliths seem to cause appendicitis. Because the presence of appendicolith influences the treatment decisions, there is a need to standardize their radiological diagnosis and better understand their pathophysiology.
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Scheduling rotations for a pathology training program involves balancing educational requirements, service coverage, and paid time off (PTO). Absences can affect training as residents cross-cover, managing multiple services at once. Other specialties utilize a "Jeopardy" based system for covering absences. In this system, residents on outpatient services are "jeopardized" to cover inpatient services for trainee absences. Borrowing this concept, we created a schedule model with a "Jeopardy-Elective" (JE) rotation to support resident absences. Prior to 2018-19, our residency program consisted of a 12 month-long rotation schedule. We adopted a 13 four-week block rotation model system, adding four JE rotations per resident over the course of training. The JE resident covered services during trainee absences and spent the remaining rotation on elective. We then conducted a pre- and post-intervention survey of all residents who trained in both systems. Following the change in schedule model, our results showed a statistically significant increase in resident satisfaction with taking PTO (p = 0.0014), finding coverage (p = 0.0006), and taking a sick day (p = 0.03). The mean number of days covered by the JE resident was 8.5 ± 2.7 workdays (out of 20). PTO usage increased from 16 to 20 days/resident while mean number of sick days decreased from 1.7 to 1.3 days per resident. There was overwhelming support with 82% of residents wanting to retain the new system going forward. Through use of the JE rotation, our program improved service coverage issues and resident satisfaction, with the long-term goal of enhanced resident well-being and enriched resident learning experiences.
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Background: The molecular mechanisms underlying Fontan associated liver disease (FALD) remain largely unknown. We aimed to assess intrahepatic transcriptomic differences among patients with FALD according to the degree of liver fibrosis and clinical outcomes. Methods: This retrospective cohort study included adults with the Fontan circulation at the Ahmanson/UCLA Adult Congenital Heart Disease Center. Clinical, laboratory, imaging and hemodynamic data prior to the liver biopsy were extracted from medical records. Patients were classified into early (F1-F2) or advanced fibrosis (F3-F4). RNA was isolated from formalin-fixed paraffin embedded liver biopsy samples; RNA libraries were constructed using rRNA depletion method and sequencing was performed on Illumina Novaseq 6000. Differential gene expression and gene ontology analyses were carried out using DESeq2 and Metascape. Medical records were comprehensively reviewed for a composite clinical outcome which included decompensated cirrhosis, hepatocellular carcinoma, liver transplantation, protein-losing enteropathy, chronic kidney disease stage 4 or higher, or death. Results: Patients with advanced fibrosis had higher serum BNP levels and Fontan, mean pulmonary artery and capillary wedge pressures. The composite clinical outcome was present in 23 patients (22%) and was predicted by age at Fontan, right ventricular morphology and presence of aortopulmonary collaterals on multivariable analysis. Samples with advanced fibrosis had 228 up-regulated genes compared to early fibrosis. Samples with the composite clinical outcome had 894 up-regulated genes compared to those without it. A total of 136 up-regulated genes were identified in both comparisons and these genes were enriched in cellular response to cytokine stimulus, response to oxidative stress, VEGFA-VEGFR2 signaling pathway, TGF-beta signaling pathway, and vasculature development. Conclusions: Patients with FALD and advanced liver fibrosis or the composite clinical outcome exhibit up-regulated genes including pathways related to inflammation, congestion, and angiogenesis. This adds further insight into FALD pathophysiology.
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Hepatocellular adenomas (HCAs) are a family of liver tumors that are associated with variable prognoses. Since the initial description of these tumors, the classification of HCAs has expanded and now includes eight distinct genotypic subtypes based on molecular analysis findings. These genotypic subtypes have unique derangements in their cellular biologic makeup that determine their clinical course and may allow noninvasive identification of certain subtypes. Multiphasic MRI performed with hepatobiliary contrast agents remains the best method to noninvasively detect, characterize, and monitor HCAs. HCAs are generally hypointense during the hepatobiliary phase; the ß-catenin-mutated exon 3 subtype and up to a third of inflammatory HCAs are the exception to this characterization. It is important to understand the appearances of HCAs beyond their depictions at MRI, as these tumors are typically identified with other imaging modalities first. The two most feared related complications are bleeding and malignant transformation to hepatocellular carcinoma, although the risk of these complications depends on tumor size, subtype, and clinical factors. Elective surgical resection is recommended for HCAs that are persistently larger than 5 cm, adenomas of any size in men, and all ß-catenin-mutated exon 3 HCAs. Thermal ablation and transarterial embolization are potential alternatives to surgical resection. In the acute setting of a ruptured HCA, patients typically undergo transarterial embolization with or without delayed surgical resection. This update on HCAs includes a review of radiologic-pathologic correlations by subtype and imaging modality, related complications, and management recommendations. © RSNA, 2023 Online supplemental material is available for this article. Quiz questions for this article are available through the Online Learning Center.
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Adenoma de Células Hepáticas , Adenoma , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Adenoma de Células Hepáticas/patología , beta Catenina , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Imagen por Resonancia Magnética/métodosRESUMEN
CONTEXT.: Cytomegalovirus (CMV) hepatitis in allograft livers is an important infectious complication, with histology that historically has been described to overlap with that of acute cellular rejection (ACR), a diagnosis that compels a different treatment regimen. OBJECTIVE.: To update the clinicopathologic features of CMV hepatitis and explore its clinical and histologic relationship with ACR. DESIGN.: A retrospective analysis of 26 patients with a diagnosis of CMV hepatitis across 4 institutions was performed, including clinical, histologic, and immunohistochemical features. RESULTS.: Patients were predominantly CMV donor positive/recipient negative (D+/R-; n = 9 of 15) and received a diagnosis of CMV hepatitis at a mean age of 52 years (SD, 17 years), at a mean interval of 184 days (SD, 165 days) from transplantation. Mean CMV viral load at diagnosis was 241 000 IU/mL (SD, 516 000 IU/mL), and liver biochemical enzymes were elevated (mean alanine aminotransferase, 212 U/L [SD, 180 U/L]; mean aspartate aminotransferase, 188 U/L [SD, 151 U/L]; mean alkaline phosphatase, 222 U/L [SD, 153 U/L]). Ten cases did not show histologic features of ACR, and 16 cases demonstrated features of ACR (including marked bile duct injury and endotheliitis). Viral cytopathic change was found in all cases. All patients were treated with a combination of antiviral therapy and CMV intravenous immunoglobulin, with near resolution of biochemical enzymes in all patients with undetectable serum CMV viral titers. CONCLUSIONS.: CMV hepatitis and ACR are complex processes with interlinking mechanisms that are important to distinguish. A subset of transplantation patients with CMV hepatitis show histologic changes that mimic ACR but were treated successfully with antiviral therapy alone.
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Infecciones por Citomegalovirus , Hepatitis , Trasplante de Hígado , Humanos , Persona de Mediana Edad , Citomegalovirus , Estudios Retrospectivos , Trasplante de Hígado/efectos adversos , Infecciones por Citomegalovirus/diagnóstico , Infecciones por Citomegalovirus/tratamiento farmacológico , Rechazo de Injerto/diagnóstico , Antivirales/uso terapéutico , Hepatitis/diagnóstico , Hepatitis/complicaciones , Hepatitis/tratamiento farmacológico , AloinjertosRESUMEN
BACKGROUND: Solid organ transplantation is the therapy of choice for many patients with end-stage organ failure; however, recipients must remain on lifelong immunosuppression, leaving them susceptible to infections and cancer. The study of transplant tolerance to prolong graft survival in the absence of immunosuppression has been restricted to recipients of living donor allografts; however, deceased donors significantly outnumber living donors. Mobilization of hematopoietic stem cells (HSCs) from the bone marrow to peripheral blood (PB) could allow PB-HSCs to be used to induce tolerance in deceased donor kidney recipients; however, a major concern is the well-known concomitant mobilization of immune cells into the liver. METHODS: We mobilized HSCs to the PD using a protocol of 2 doses of granulocyte colony-stimulating factor and 1 dose of plerixafor, followed by the collection of mobilized cells via apheresis in 3 deceased donors. The physiological, laboratory, and radiographic parameters were monitored throughout the procedure. Longitudinal biopsies were performed to assess the potential for ectopic liver mobilization. RESULTS: The use of both agents led to the successful mobilization of peripheral blood CD34+ cells, demonstrating the potential for use in transplant tolerance protocols. Increased immune cell trafficking into the liver was not observed, and apheresis of mobilized cells resulted in a uniform decrease in all liver leukocyte subsets. CONCLUSIONS: HSCs can be mobilized and collected from the PB of brain-dead donors. This new approach may facilitate the dissemination of immune tolerance trials beyond living-donor kidney transplantation to deceased-donor transplantation, without sacrificing the transplantability of the liver.
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Eliminación de Componentes Sanguíneos , Trasplante de Células Madre Hematopoyéticas , Compuestos Heterocíclicos , Humanos , Movilización de Célula Madre Hematopoyética/métodos , Células Madre Hematopoyéticas , Antígenos CD34/metabolismo , Factor Estimulante de Colonias de Granulocitos/farmacología , Donadores Vivos , Trasplante de Células Madre Hematopoyéticas/efectos adversosRESUMEN
BACKGROUND. The classification of hepatocellular adenomas (HCAs) was updated in 2017 on the basis of genetic and molecular analysis. OBJECTIVE. The purpose of this article was to evaluate features on gadoxetate disodium-enhanced MRI of HCA subtypes on the basis of the 2017 classification and to propose a diagnostic algorithm for determining subtype using these features. METHODS. This retrospective study included 56 patients (49 women, seven men; mean age, 37 ± 13 [SD] years) with histologically confirmed HCA evaluated by gadoxetate disodium-enhanced MRI from January 2010 to January 2021. Subtypes were reclassified using 2017 criteria: hepatocyte nuclear factor-1α mutated HCA (HHCA), inflammatory HCA (IHCA), ß-catenin exon 3 activated HCA (ß-HCA), mixed inflammatory and ß-HCA (ß-IHCA), sonic hedgehog HCA (shHCA), and unclassified HCA (UHCA). Qualitative MRI features were assessed. Liver-to-lesion contrast enhancement ratios (LLCERs) were measured. Subtypes were compared, and a diagnostic algorithm was proposed. RESULTS. The analysis included 65 HCAs: 16 HHCAs, 31 IHCAs, six ß-HCA, four ß-IHCA, five shHCA, and three UHCAs. HHCAs showed homogeneous diffuse intralesional steatosis in 94%, whereas all other HCAs showed this finding in 0% (p < .001). IHCAs showed the "atoll" sign in 58%, whereas all other HCAs showed this finding in 12% (p < .001). IHCAs showed moderate T2 hyperintensity in 52%, whereas all other HCAs showed this finding in 12% (p < .001). The ß-HCAs and ß-IHCAs occurred in men in 63%, whereas all other HCAs occurred in men in 4% (p < .001). The ß-HCAs and ß-IHCAs had a mean size of 10.1 ± 6.8 cm, whereas all other HCAs had a mean size of 5.1 ± 2.9 cm (p = .03). The ß-HCAs and ß-IHCAs showed fluid components in 60%, whereas all other HCAs showed this finding in 5% (p < .001). Hepatobiliary phase iso- or hyperintensity was observed in 80% of ß-HCAs and ß-IHCAs versus 5% of all other HCAs (p < .001). Hepatobiliary phase LLCER was positive in nine HCAs (eight ß-HCAs and ß-IHCAs; one IHCA). The shHCA and UHCA did not show distinguishing features. The proposed diagnostic algorithm had accuracy of 98% for HHCAs, 83% for IHCAs, and 95% for ß-HCAs or ß-IHCAs. CONCLUSION. Findings on gadoxetate disodium-enhanced MRI, including hepatobiliary phase characteristics, were associated with HCA subtypes using the 2017 classification. CLINICAL IMPACT. The algorithm identified common HCA subtypes with high accuracy, including those with ß-catenin exon 3 mutations.
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Adenoma de Células Hepáticas , Carcinoma Hepatocelular , Neoplasias Hepáticas , Masculino , Humanos , Femenino , Adulto Joven , Adulto , Persona de Mediana Edad , Adenoma de Células Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/diagnóstico por imagen , Carcinoma Hepatocelular/patología , beta Catenina , Estudios Retrospectivos , Medios de Contraste , Proteínas Hedgehog , Imagen por Resonancia Magnética/métodosRESUMEN
Immunosuppression withdrawal can be safely performed in select liver transplantation recipients, but the long-term outcomes and sustainability of tolerance have not been well studied. We completed a 10-year prospective, observational study of 18 pediatric liver transplantation recipients with operational tolerance to (1) assess the sustainability of tolerance over time, (2) compare the clinical characteristics of patients who maintained versus lost tolerance, (3) characterize liver histopathology findings in surveillance liver biopsies; and (4) describe immunologic markers in patients with tolerance. Comparator patients from two clinical phenotype groups termed "stable" and "nontolerant" patients were used as controls. Of the 18 patients with operational tolerance, the majority of patients were males (n = 14, 78%) who were transplanted for cholestatic liver disease (n = 12, 67%). Median age at transplantation was 1.9 (range, 0.6-8) years. Median time after transplantation that immunosuppression had been discontinued was 13.1 (range, 2.9-22.1) years. As many as 11 (61%) maintained tolerance for a median of 10.4 (range, 1.9-22.1) years, whereas 7 (39%) lost tolerance after a median of 3.2 (range, 1.5-18.6) years. Populations of T regulatory cells (%CD4+ CD25hi CD127lo ) were significantly higher in patients with tolerance (p = 0.02). Our results emphasize that spontaneous operational tolerance is a dynamic and nonpermanent state. It is therefore essential for patients who are clinically stable off immunosuppression to undergo regular follow-up and laboratory monitoring, as well as surveillance biopsies to rule out subclinical rejection.
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Trasplante de Hígado , Biomarcadores , Femenino , Rechazo de Injerto/prevención & control , Humanos , Tolerancia Inmunológica , Inmunosupresores/efectos adversos , Hígado/cirugía , Trasplante de Hígado/efectos adversos , Trasplante de Hígado/métodos , Masculino , Estudios Prospectivos , Tolerancia al TrasplanteRESUMEN
Purpose: To report a case of hypertensive granulomatous anterior uveitis in the setting of IgG4-related disease (IgG4-RD). Observations: A 69-year-old man presented with no light perception vision in both eyes and bilateral granulomatous anterior uveitis with iris neovascularization and hyphema in the right eye. He also demonstrated concurrent polyuria, polydipsia, and altered mental status, and was diagnosed with new-onset diabetes mellitus. MRI revealed no orbital abnormalities, but showed bilateral occipital strokes attributed to hyperglycemic hyperosmolar syndrome. Chest CT revealed pleural-based nodules and mediastinal and abdominal lymphadenopathy, and a liver biopsy confirmed fibroinflammatory nodules with increased IgG4 positive plasma cell infiltrates, diagnostic of IgG4-RD. Serum IgG4 levels were 1381 mg/dL. The patient was treated with a combination of systemic and topical steroids, and later initiated on rituximab. Conclusion and importance: IgG4-related ophthalmic disease may present as an isolated hypertensive granulomatous anterior uveitis without associated scleral or orbital involvement.
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CONTEXT.: Comprehensive genomic profiling has demonstrated that approximately 20% of pancreatic carcinomas with acinar differentiation harbor potentially targetable BRAF fusions that activate the MAPK pathway. OBJECTIVES.: To validate the above finding by BRAF break-apart fluorescence in situ hybridization (FISH) in a large series of pure acinar cell carcinomas (ACCs), evaluate tumors for the presence of BRAF V600E mutations, and compare clinicopathologic features of tumors with BRAF rearrangements with those without. DESIGN.: Thirty cases of pure ACC and 6 cases of mixed acinar-neuroendocrine carcinoma (ACC-NEC) were retrieved. A break-apart FISH probe was used to detect BRAF rearrangements. Immunohistochemistry for BRAF V600E was performed. RESULTS.: BRAF rearrangements by FISH were found in 6 of 36 cases (17%), 5 of which were pure ACC and 1 was a mixed ACC-NEC. Follow-up was available in 29 of 36 cases (81%). The median survival was 22 months for BRAF-rearranged cases and 16 months for BRAF-intact cases; the 2-year overall survival was 50% for BRAF-rearranged cases and 35% for BRAF-intact cases. No significant clinicopathologic differences were identified in cases with BRAF rearrangement compared with those without BRAF rearrangement. BRAF V600E mutation was identified in 2 of 34 cases (6%), both of which were pure ACC and were BRAF-intact by FISH. CONCLUSIONS.: This study supports the finding that BRAF rearrangements are present in approximately 20% of cases and identified BRAF V600E mutations in approximately 5% of cases. These cases may benefit from targeted therapy.
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Carcinoma de Células Acinares , Carcinoma Neuroendocrino , Neoplasias Pancreáticas , Carcinoma de Células Acinares/genética , Carcinoma de Células Acinares/patología , Carcinoma Neuroendocrino/genética , Carcinoma Neuroendocrino/patología , Humanos , Hibridación Fluorescente in Situ/métodos , Mutación , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias PancreáticasRESUMEN
BACKGROUND AND AIMS: Determining surveillance intervals for patients with colorectal polyps is critical but time-consuming and challenging to do reliably. We present the development and assessment of a pipeline that leverages natural language processing techniques to automatically extract and analyze relevant polyp findings from free-text colonoscopy and pathology reports. Using this information, we categorized individual patients into 6 postcolonoscopy surveillance intervals defined by the U.S. Multi-Society Task Force on Colorectal Cancer. METHODS: Using a set of 546 randomly selected colonoscopy and pathology reports from 324 patients in a single health system, we used a combination of statistical classifiers and rule-based methods to extract polyp properties from each report type, associate properties with unique polyps, and classify a patient into 1 of 6 risk categories by integrating information from both report types. We then assessed the pipeline's performance by determining the positive predictive value (PPV), sensitivity, and F-score of the algorithm, compared with the determination of surveillance intervals by a gastroenterologist. RESULTS: The pipeline was developed using 346 reports (224 colonoscopy and 122 pathology) from 224 patients and evaluated on an independent test set of 200 reports (100 colonoscopy and 100 pathology) from 100 patients. We achieved an average PPV, sensitivity, and F-score of .92, .95, and .93, respectively, across targeted entities for colonoscopy. Pathology extraction achieved a PPV, sensitivity, and F-score of .95, .97, and .96. The system achieved an overall accuracy of 92% in assigning the recommended interval for surveillance colonoscopy. CONCLUSIONS: This study demonstrates the feasibility of using machine learning to automatically extract findings and classify patients to appropriate risk categories and corresponding surveillance intervals. Incorporating this system can facilitate proactive and timely follow-up after screening colonoscopy and enable real-time quality assessment of prevention programs and providers.
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Pólipos del Colon , Neoplasias Colorrectales , Gastroenterólogos , Pólipos del Colon/diagnóstico por imagen , Colonoscopía , Neoplasias Colorrectales/diagnóstico , Humanos , Tamizaje Masivo , Procesamiento de Lenguaje NaturalRESUMEN
Monitoring of intestinal allograft function remains a challenge. While frequent endoscopies and biopsies are the gold standard, no single biomarker exists to screen for intestinal transplant rejection. The novel REG3α, an antimicrobial peptide secreted by intestinal enterocytes and Paneth cells, has been associated with inflammatory bowel disease as well as intestinal graft versus host disease. Our aim was to identify and describe a role of REG3α in monitoring or predicting acute allograft rejection after intestinal transplantation (ITx). Since 2019, we have incorporated REG3α into the standard monitoring of patients after ITx. We conducted a retrospective analysis of a prospectively maintained IRB-approved database and present, herein, the results of 2 adults with irreversible intestinal failure who underwent isolated ITx under this monitoring protocol. Increases in REG3α corresponded with acute allograft rejection in both cases and preceded acute allograft rejection by 1 week in one of the cases. We describe REG3α as a non-invasive marker of acute allograft rejection after adult isolated ITx which not only corresponded with acute allograft rejection but also preceded histopathological changes by 1 week.
Asunto(s)
Rechazo de Injerto , Adulto , Aloinjertos , Biomarcadores , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/etiología , Humanos , Estudios Retrospectivos , Trasplante HomólogoRESUMEN
BACKGROUND AND AIMS: Environmentally triggered chronic liver inflammation can cause collagen deposits, whereas early stages of fibrosis without any specific symptoms could hardly be detectable. We hypothesized that some of the human donor grafts in clinical liver transplantation (LT) might possess unrecognizable fibrosis, affecting their susceptibility to LT-induced stress and hepatocellular damage. This retrospective study aimed to assess the impact of occult hepatic fibrosis on clinical LT outcomes. APPROACH AND RESULTS: Human (194) donor liver biopsies were stained for collagen with Sirius red, and positive areas (Sirius red-positive area; SRA) were measured. The body mass index, aspartate aminotransferase/alanine aminotransferase ratio, diabetes score was calculated using 962 cases of the donor data at the procurement. LT outcomes, including ischemia-reperfusion injury (IRI), early allograft dysfunction (EAD), and survival rates, were analyzed according to SRA and BARD scores. With the median SRA in 194 grafts of 9.4%, grafts were classified into low-SRA (<15%; n = 140) and high-SRA (≥15%; n = 54) groups. Grafts with high SRA suffered from higher rates of IRI and EAD (P < 0.05) as compared to those with low SRA. Interestingly, high SRA was identified as an independent risk factor for EAD and positively correlated with the donor BARD score. When comparing low-BARD (n = 692) with high-BARD (n = 270) grafts in the same period, those with high BARD showed significantly higher post-LT transaminase levels and higher rates of IRI and EAD. CONCLUSIONS: These findings from the largest clinical study cohort to date document the essential role of occult collagen deposition in donor livers on LT outcomes. High-SRA and donor BARD scores correlated with an increased incidence of hepatic IRI and EAD in LT recipients. This study provides the rationale for in-depth and prospective assessment of occult fibrosis for refined personalized LT management.
Asunto(s)
Colágeno/análisis , Selección de Donante/métodos , Cirrosis Hepática/diagnóstico , Trasplante de Hígado/efectos adversos , Disfunción Primaria del Injerto/epidemiología , Adolescente , Adulto , Anciano , Aloinjertos/patología , Biopsia , Femenino , Supervivencia de Injerto , Humanos , Incidencia , Hígado/patología , Cirrosis Hepática/complicaciones , Cirrosis Hepática/patología , Masculino , Persona de Mediana Edad , Disfunción Primaria del Injerto/etiología , Disfunción Primaria del Injerto/prevención & control , Estudios Prospectivos , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND AND AIMS: Liver ischemia reperfusion injury (IRI) remains an unresolved clinical problem. This study dissected roles of liver-resident macrophage Kupffer cells (KCs), with a functional focus on efferocytosis receptor T-cell immunoglobulin and mucin domain-containing protein-4 (TIM-4), in both the activation and resolution of IRI in a murine liver partial warm ischemia model. APPROACH AND RESULTS: Fluorescence-activated cell sorting results showed that TIM-4 was expressed exclusively by KCs, but not infiltrating macrophages (iMФs), in IR livers. Anti-TIM-4 antibody depleted TIM-4+ macrophages in vivo, resulting in either alleviation or deterioration of liver IRI, which was determined by the repopulation kinetics of the KC niche with CD11b+ macrophages. To determine the KC-specific function of TIM-4, we reconstituted clodronate-liposome-treated mice with exogenous wild-type or TIM-4-deficient KCs at either 0 hour or 24 hours postreperfusion. TIM-4 deficiency in KCs resulted in not only increases in the severity of liver IRI (at 6 hours postreperfusion), but also impairment of the inflammation resolution (at 7 days postreperfusion). In vitro analysis revealed that TIM-4 promoted KC efferocytosis to regulate their Toll-like receptor response by up-regulating IL-10 and down-regulating TNF-α productions. CONCLUSIONS: TIM-4 is critical for KC homeostatic function in both the activation and resolution of liver IRI by efferocytosis.