Browsing by Subject "liver"
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Item 90Y Radioembolization for Hepatic Malignancy in Patients with Previous Biliary Intervention: Multicenter Analysis of Hepatobiliary Infections(Radiological Society of North America, 2018-05-08) Devulapalli, Kavi K.; Fidelman, Nicholas; Soulen, Michael C.; Miller, Matthew; Johnson, Matthew S.; Addo, Eric; El-Haddad, Ghassan; Nutting, Charles; Morrison, James; Farsad, Khashayar; Lokken, R. Peter; Gaba, Ron C.; Fleming, Jacob; Brown, Daniel B.; Kwan, Sharon W.; Rose, Steven C.; Pennycooke, Kevin A.; Liu, David M.; White, Sarah B.; Gandhi, Ripal; Lazar, Ann A.; Kerlan, Robert K.; Radiology and Imaging Sciences, School of MedicinePurposeTo determine the frequency of hepatobiliary infections after transarterial radioembolization (TARE) with yttrium 90 (90Y) in patients with liver malignancy and a history of biliary intervention.Materials and MethodsFor this retrospective study, records of all consecutive patients with liver malignancy and history of biliary intervention treated with TARE at 14 centers between 2005 and 2015 were reviewed. Data regarding liver function, 90Y dosimetry, antibiotic prophylaxis, and bowel preparation prophylaxis were collected. Primary outcome was development of hepatobiliary infection.ResultsOne hundred twenty-six patients (84 men, 42 women; mean age, 68.8 years) with primary (n = 39) or metastatic (n = 87) liver malignancy and history of biliary intervention underwent 180 procedures with glass (92 procedures) or resin (88 procedures) microspheres. Hepatobiliary infections (liver abscesses in nine patients, cholangitis in five patients) developed in 10 of the 126 patients (7.9%) after 11 of the 180 procedures (6.1%; nine of those procedures were performed with glass microspheres). All patients required hospitalization (median stay, 12 days; range, 2–113 days). Ten patients required percutaneous abscess drainage, three patients underwent endoscopic stent placement and stone removal, and one patient needed insertion of percutaneous biliary drains. Infections resolved in five patients, four patients died (two from infection and two from cancer progression while infection was being treated), and one patient continued to receive suppressive antibiotics. Use of glass microspheres (P = .02), previous liver resection or ablation (P = .02), and younger age (P = .003) were independently predictive of higher infection risk.ConclusionInfectious complications such as liver abscess and cholangitis are uncommon but serious complications of transarterial radioembolization with 90Y in patients with liver malignancy and a history of biliary intervention.© RSNA, 2018Online supplemental material is available for this article.Item Change in Platelet Count after Transjugular Intrahepatic Portosystemic Shunt Creation: An Advancing Liver Therapeutic Approaches (ALTA) Group Study(Elsevier, 2023) Wong, Randi J.; Ge, Jin; Boike, Justin; German, Margarita; Morelli, Giuseppe; Spengler, Erin; Said, Adnan; Desai, Archita; Couri, Thomas; Paul, Sonali; Frenette, Catherine; Verna, Elizabeth C.; Goel, Aparna; Fallon, Michael; Thornburg, Bartley; VanWagner, Lisa; Lai, Jennifer C.; Kolli, K. Pallav; Medicine, School of MedicinePurpose To evaluate recovery of platelet count after transjugular intrahepatic portosystemic shunt (TIPS) creation and patient factors predicting platelet recovery after TIPS creation. Materials and Methods Adults with cirrhosis who underwent TIPS creation at 9 U.S. hospitals from 2010 to 2015 were included in this retrospective analysis. Change in platelets from before TIPS to 4 months after TIPS creation was characterized. Logistic regression was used to assess factors associated with top quartile percentage platelet increase after TIPS. Subgroup analyses were performed among patients with a pre-TIPS platelet count of ≤50 ×109/L. Results A total of 601 patients were included. The median absolute change in platelets was 1 × 109/L (−26 × 109/L to 25 × 109/L). Patients with top quartile percent platelet increase experienced ≥32% platelet increase. In multivariable analysis, pre-TIPS platelet counts (odds ratio [OR], 0.97 per 109/L; 95% CI, 0.97–0.98), age (OR, 1.24 per 5 years; 95% CI, 1.10–1.39), and pre-TIPS model for end-stage liver disease (MELD) scores (OR, 1.06 per point; 95% CI, 1.02–1.09) were associated with top quartile (≥32%) platelet increase. Ninety-four (16%) patients had a platelet count of ≤50 × 109/L before TIPS. The median absolute platelet change was 14 × 109/L (2 × 109/L to 34 × 109/L). Fifty-four percent of patients in this subgroup were in the top quartile for platelet increase. In multivariable logistic regression, age (OR, 1.50 per 5 years; 95% CI, 1.11–2.02) was the only factor associated with top quartile platelet increase in this subgroup. Conclusions TIPS creation did not result in significant platelet increase, except among patients with a platelet count of ≤50 × 109/L before TIPS. Lower pre-TIPS platelet counts, older age, and higher pre-TIPS MELD scores were associated with top quartile (≥32%) platelet increase in the entire cohort, whereas only older age was associated with this outcome in the patient subset with a pre-TIPS platelet count of ≤50 × 109/L.Item Development and Validation of Model Consisting of Comorbidity Burden to Calculate Risk of Death Within 6 months for Patients With Suspected Drug-Induced Liver Injury(Elsevier, 2019-11) Ghabril, Marwan; Gu, Jiezhun; Yoder, Lindsay; Corbito, Laura; Ringel, Amit; Beyer, Christian D.; Vuppalanchi, Raj; Barnhart, Huiman; Hayashi, Paul H.; Chalasani, Naga; Medicine, School of MedicineBackground & Aims: Patients with drug-induced liver injury (DILI) frequently have comorbid conditions, but the effects of non-liver comorbidities on outcome is not well understood. We investigated the association between co-morbidity burden and outcomes of patients with DILI, and developed and validated a model to calculate risk of death within 6 months. Methods: A multiple logistic regression model identified variables independently associated with death within 6 months of presenting with suspected DILI (6-month mortality) for 306 patients enrolled in the DILIN prospective study at Indiana University (discovery cohort). The model was validated using data from 247 patients with suspected DILI enrolled in the same study at the University of North Carolina (validation cohort). Medical comorbidity burden was calculated using the Charlson comorbidity index—patients with scores higher than 2 were considered to have significant comorbidities. Results: Six-month mortality was 8.5% in the discovery cohort and 4.5% in the validation cohort. In the discovery cohort, significant comorbidities (odds ratio [OR], 5.4; 95% CI 2.1 – 13.8), model for end-stage liver disease score (OR, 1.11; 95% CI, 1.04–1.17), and serum level of albumin at presentation (OR, 0.39; 95% CI, 0.2–0.76) were independently associated with 6-month mortality. A model based on these 3 variables identified patients who died within 6 months with c-statistic values of 0.89 (95% CI, 0.86–0.94) in the discovery cohort and 0.91 (95% CI, 0.83–0.99) in the validation cohort. We developed a web-based calculator to determine risk of death within 6 months for patients with suspected DILI for use in the clinic. Conclusions: We developed and validated a model based on comorbidity burden, model for end-stage liver disease score, and serum level of albumin that predicts 6-month mortality in patients with suspected DILI.Item Diagnosis and Follow-up of Incidental Liver Lesions in Children(Wolters Kluwer, 2022-03) Karmazyn, Boaz; Rao, Girish S.; Johnstone, Lindsey S.; Severance, Tyler S.; Ferguson, Michael J.; Marshalleck, Francis E.; Molleston, Jean P.; Radiology and Imaging Sciences, School of MedicineABSTRACT: Incidental liver lesions are identified in children without underlying liver disease or increased risk of hepatic malignancy in childhood. Clinical and imaging evaluation of incidental liver lesions can be complex and may require a multidisciplinary approach. This review aims to summarize the diagnostic process and follow-up of incidental liver lesions based on review of the literature, use of state-of-the-art imaging, and our institutional experience. Age at presentation, gender, alpha fetoprotein levels, tumor size, and imaging characteristics should all be taken into consideration to optimize diagnosis process. Some lesions, such as simple liver cyst, infantile hemangioma, focal nodular hyperplasia (FNH) and focal fatty lesions, have specific imaging characteristics. Recently, contrast-enhanced ultrasound (CEUS) was FDA-approved for the evaluation of pediatric liver lesions. CEUS is most specific in lesions smaller than 3 cm and is most useful in the diagnosis of infantile hemangioma, FNH, and focal fatty lesions. The use of hepatobiliary contrast in MRI increases specificity in the diagnosis of FNH. Recently, lesion characteristics in MRI were found to correlate with subtypes of hepatocellular adenomas and associated risk for hemorrhage and malignant transformation. Biopsy should be considered when there are no specific imaging characteristics of a benign lesion. Surveillance with imaging and AFP should be performed to confirm the stability of lesions when the diagnosis cannot be determined, and when biopsy is not feasible.Item Effect of developmental stage of HSC and recipient on transplant outcomes(Elsevier, 2014-06-09) Arora, Natasha; Wenzel, Pamela L.; McKinney-Freeman, Shannon L.; Ross, Samantha J.; Kim, Peter G.; Chou, Stephanie S.; Yoshimoto, Momoko; Yoder, Mervin C.; Daley, George Q.; Department of Pediatrics, IU School of MedicineThe first hematopoietic stem cells (HSCs) that engraft irradiated adult mice arise in the aorta-gonad-mesonephros (AGM) on embryonic day 11.5 (E11.5). However, at this stage, there is a discrepancy between the apparent frequency of HSCs depicted with imaging and their rarity when measured with limiting dilution transplant. We have attempted to reconcile this difference using neonatal recipients, which are more permissive for embryonic HSC engraftment. We found that embryonic HSCs from E9.5 and E10.5 preferentially engrafted neonates, whereas developmentally mature, definitive HSCs from E14.5 fetal liver or adult bone marrow (BM) more robustly engrafted adults. Neonatal engraftment was enhanced after treating adult BM-derived HSCs with interferon. Adult BM-derived HSCs preferentially homed to the liver in neonatal mice yet showed balanced homing to the liver and spleen in adults. These findings emphasize the functional differences between nascent and mature definitive HSCs.Item Effect of oral methyl-t-butyl ether (MTBE) on the male mouse reproductive tract and oxidative stress in liver(Elsevier, 2008) de Peyster, Ann; Rodriguez, Yvonne; Shuto, Rika; Goldberg, Beck; Gonzales, Frank; Pu, Xinzhu; Klaunig, James E.; Department of Pharmacology and Toxicology, IU School of MedicineMTBE is found in water supplies used for drinking and other purposes. These experiments follow up on earlier reports of reproductive tract alterations in male mice exposed orally to MTBE and explored oxidative stress as a mode of action. CD-1 mice were gavaged with 400–2000 mg/kg MTBE on days 1, 3, and 5, injected ip with hCG (2.5 IU/g) on day 6, and necropsied on day 7. No effect was seen in testis histology or testosterone levels. Using a similar dosing protocol, others had initially reported disruption of seminiferous tubules in MTBE–gavaged mice, although later conclusions published were consistent with our findings. Another group had also reported testicular and other reproductive system abnormalities in male BALB/c mice exposed for 28 days to 80–8000 ug/ml MTBE in drinking water. We gave these MTBE concentrations to adult mice for 28 days and juvenile mice for 51 days through PND 77. Evidence of oxidative stress was examined in liver homogenates from the juvenile study using MDA, TEAC and 8OH2hG as endpoints. MTBE exposures at the levels examined indicated no significant changes in the male mouse reproductive tract and no signs of hepatic oxidative stress. This appears to be the first oral MTBE exposure of juvenile animals, and also the first to examine potential for MTBE to cause oxidative stress in vivo using a typical route of human exposure.Item Experimental Variables that Affect Human Hepatocyte AAV Transduction in Liver Chimeric Mice(Elsevier, 2020-09-11) Zou, Chenhui; Vercauteren, Koen O. A.; Michailidis, Eleftherios; Kabbani, Mohammad; Zoluthkin, Irene; Quirk, Corrine; Chiriboga, Luis; Yazicioglu, Mustafa; Anguela, Xavier M.; Meuleman, Philip; High, Katherine A.; Herzog, Roland W.; Jong, Ype P. de; Pediatrics, School of MedicineAdeno-associated virus (AAV) vector serotypes vary in their ability to transduce hepatocytes from different species. Chimeric mouse models harboring human hepatocytes have shown translational promise for liver-directed gene therapies. However, many variables that influence human hepatocyte transduction and transgene expression in such models remain poorly defined. Here, we aimed to test whether three experimental conditions influence AAV transgene expression in immunodeficient, fumaryl-acetoactetate-hydrolase-deficient (Fah−/−) chimeric mice repopulated with primary human hepatocytes. We examined the effects of the murine liver injury cycle, human donor variability, and vector doses on hepatocyte transduction with various AAV serotypes expressing a green fluorescent protein (GFP). We determined that the timing of AAV vector challenge in the liver injury cycle resulted in up to 7-fold differences in the percentage of GFP expressing human hepatocytes. The GFP+ hepatocyte frequency varied 7-fold between human donors without, however, changing the relative transduction efficiency between serotypes for an individual donor. There was also a clear relationship between AAV vector doses and human hepatocyte transduction and transgene expression. We conclude that several experimental variables substantially affect human hepatocyte transduction in the Fah−/− chimera model, attention to which may improve reproducibility between findings from different laboratories.Item IL-15 blockade and rapamycin rescue multifactorial loss of factor VIII from AAV-transduced hepatocytes in hemophilia A mice(Elsevier, 2022-12-07) Butterfield, John S. S.; Yamada, Kentaro; Bertolini, Thais B.; Syed, Farooq; Kumar, Sandeep R. P.; Li, Xin; Arisa, Sreevani; Piñeros, Annie R.; Tapia, Alejandro; Rogers, Christopher A.; Li, Ning; Rana, Jyoti; Biswas, Moanaro; Terhorst, Cox; Kaufman, Randal J.; de Jong, Ype P.; Herzog, Roland W.; Pediatrics, School of MedicineHepatic adeno-associated viral (AAV) gene transfer has the potential to cure the X-linked bleeding disorder hemophilia A. However, declining therapeutic coagulation factor VIII (FVIII) expression has plagued clinical trials. To assess the mechanistic underpinnings of this loss of FVIII expression, we developed a hemophilia A mouse model that shares key features observed in clinical trials. Following liver-directed AAV8 gene transfer in the presence of rapamycin, initial FVIII protein expression declines over time in the absence of antibody formation. Surprisingly, loss of FVIII protein production occurs despite persistence of transgene and mRNA, suggesting a translational shutdown rather than a loss of transduced hepatocytes. Some of the animals develop ER stress, which may be linked to hepatic inflammatory cytokine expression. FVIII protein expression is preserved by interleukin-15/interleukin-15 receptor blockade, which suppresses CD8+ T and natural killer cell responses. Interestingly, mice with initial FVIII levels >100% of normal had diminishing expression while still under immune suppression. Taken together, our findings of interanimal variability of the response, and the ability of the immune system to shut down transgene expression without utilizing cytolytic or antibody-mediated mechanisms, illustrate the challenges associated with FVIII gene transfer. Our protocols based upon cytokine blockade should help to maintain efficient FVIII expression.Item Impact of silencing hepatic SREBP-1 on insulin signaling(PLOS, 2018-05-03) Jideonwo, Victoria; Hou, Yongyong; Ahn, Miwon; Surendran, Sneha; Morral, Núria; Medical and Molecular Genetics, School of MedicineSterol Regulatory Element Binding Protein-1 (SREBP-1) is a conserved transcription factor of the basic helix-loop-helix leucine zipper family (bHLH-Zip) that plays a central role in regulating expression of genes of carbohydrate and fatty acid metabolism in the liver. SREBP-1 activity is essential for the control of insulin-induced anabolic processes during the fed state. In addition, SREBP-1 regulates expression of key molecules in the insulin signaling pathway, including insulin receptor substrate 2 (IRS2) and a subunit of the phosphatidylinositol 3-kinase (PI3K) complex, PIK3R3, suggesting that feedback mechanisms exist between SREBP-1 and this pathway. Nevertheless, the overall contribution of SREBP-1 activity to maintain insulin signal transduction is unknown. Furthermore, Akt is a known activator of mTORC1, a sensor of energy availability that plays a fundamental role in metabolism, cellular growth and survival. We have silenced SREBP-1 and explored the impact on insulin signaling and mTOR in mice under fed, fasted and refed conditions. No alterations in circulating levels of insulin were observed. The studies revealed that depletion of SREBP-1 had no impact on IRS1Y612, AktS473, and downstream effectors GSK3αS21 and FoxO1S256 during the fed state. Nevertheless, reduced levels of these molecules were observed under fasting conditions. These effects were not associated with changes in phosphorylation of mTOR. Overall, our data indicate that the contribution of SREBP-1 to maintain insulin signal transduction in liver is modest.Item Mast Cells Regulate Bile Acid Signaling and Cholestasis via Alteration of Farnesoid X Receptor/Fibroblast Growth Factor 15 Axis in Mice(2022-03) Meadows, Victoria E.; Francis, Heather; Alpini, Gianfranco; Dong, X Charlie; Esker, Burcin; Ren, HongxiaPrimary Sclerosing Cholangitis (PSC) is a rare and slow progressing cholangiopathy characterized by hepatic inflammation, fibrosis and ductular reaction with liver transplantation as the sole therapeutic option. PSC patients are at high risk of auto-immune comorbidities like irritable bowel disease (IBD), found in up to 80% of PSC patients (PSC-IBD). There are indications of genetic and environmental components for auto-immune development in IBD; however, its etiology remains unclear. Mast cells (MCs) infiltrate the liver and can become activated leading to degranulation and release of mediators, like histamine (HA), which result in increased intrahepatic bile duct mass, biliary senescence, hepatic inflammation, and hepatic stellate cell activation. Similarly, MCs infiltrate the intestine and increase inflammation which alters host-microbiome communication. MCs are necessary for successful liver regeneration and the combat of intestinal pathogens; however, chronic HA signaling exacerbates damage in cholangiopathies and IBD. Bile acid synthesis is tightly regulated by Farnesoid X Receptor (FXR) and its downstream mediator, fibroblast growth factor 15 (FGF15, -19 in humans). Cholangiocytes (i) are the target of cholangiopathies, (ii) modify and recycle bile acids through Apical Sodium Bile Acid Transporter (ASBT)-mediated cholehepatic shunting, which functions outside of enterohepatic circulation of bile acids and (iii) are capable of autocrine HA signaling. The complex relationship between hepatic and intestinal MC infiltration and bile acid signaling has not been established; therefore, identifying MC regulation of bile acid pool and FXR/FGF15 signaling pathway will provide insight into therapeutic treatment of PSC-IBD. Under the rationale that (i) cholestatic liver diseases are positively correlated with auto-immune comorbidities like IBD, (ii) during disease, MCs infiltrate the liver and intestine and release signaling factors like HA, and (iii) MCs express FXR and secrete FGF15/19; we propose the central hypothesis that MC activation regulates bile acid signaling and PSC progression through paracrine crosstalk with cholangiocytes in the liver and intestinal inflammation.