Browsing by Author "Spearman, Catherine Wendy"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Open Access
    Evaluation of encapsulated liver cell spheroids in a fluidised-bed bioartificial liver for treatment of ischaemic acute liver failure in pigs in a translational setting
    (Public Library of Science, 2013) Selden, Clare; Spearman, Catherine Wendy; Kahn, Delawir; Miller, Malcolm; Figaji, Anthony; Erro, Eloy; Bundy, James; Massie, Isobel; Chalmers, Sherri-Ann; Arendse, Hiram
    Liver failure is an increasing problem. Donor-organ shortage results in patients dying before receiving a transplant. Since the liver can regenerate, alternative therapies providing temporary liver-support are sought. A bioartificial-liver would temporarily substitute function in liver failure buying time for liver regeneration/organ-procurement. Our aim: to develop a prototype bioartificial-liver-machine (BAL) comprising a human liver-derived cell-line, cultured to phenotypic competence and deliverable in a clinical setting to sites distant from its preparation. The objective of this study was to determine whether its use would improve functional parameters of liver failure in pigs with acute liver failure, to provide proof-of-principle. HepG2cells encapsulated in alginate-beads, proliferated in a fluidised-bed-bioreactor providing a biomass of 4-6×10 10 cells, were transported from preparation-laboratory to point-of-use operating theatre (6000miles) under perfluorodecalin at ambient temperature. Irreversible ischaemic liver failure was induced in anaesthetised pigs, after portal-systemic-shunt, by hepatic-artery-ligation. Biochemical parameters, intracranial pressure, and functional-clotting were measured in animals connected in an extracorporeal bioartificial-liver circuit. Efficacy was demonstrated comparing outcomes between animals connected to a circuit containing alginate-encapsulated cells (Cell-bead BAL), and those connected to circuit containing alginate capsules without cells (Empty-bead BAL). Cells of the biomass met regulatory standards for sterility and provenance. All animals developed progressive liver-failure after ischaemia induction. Efficacy of BAL was demonstrated since animals connected to a functional biomass (+ cells) had significantly smaller rises in intracranial pressure, lower ammonia levels, more bilirubin conjugation, improved acidosis and clotting restoration compared to animals connected to the circuit without cells. In the +cell group, human proteins accumulated in pigs' plasma. Delivery of biomass using a short-term cold-chain enabled transport and use without loss of function over 3days. Thus, a fluidised-bed bioreactor containing alginate-encapsulated HepG2cell-spheroids improved important parameters of acute liver failure in pigs. The system can readily be up-scaled and transported to point-of-use justifying development at clinical scale.
  • Thumbnail Image
    Item
    Open Access
    The natural history of Efavirenz Drug Induced liver injury
    (2020) Maughan, Deborah; Spearman, Catherine Wendy; Sonderup, Mark
    Background Efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor (NNRTI), has been a component of first line antiretroviral treatment in the South African HIV/AIDS programme since 2004. Similarly, it is extensively used in ART programmes in other low and middle incomes countries. The natural history of the previously reported EFV drug induced liver injury (DILI), is unknown. Objectives To establish causality assessment for the drug-induced liver injury and elucidate the natural history of EFV DILI by observing a cohort of patients through documenting all the factors influencing the patterns of clinical and histological injury, the time to clinical and biochemical recovery, the associated mortality rate and to establish if any demographic or clinical factors predict poor outcomes. Methods Patients were prospectively included after establishing causality criteria for EFV DILI. Clinical, demographic and histological features were carefully documented from the time of presentation and through follow up. Prednisone at 0.25-0.5mg/kg was initiated at the discretion of the treating hepatologist. Risk factors for severe injury or death and time to event (full clinical recovery and full biochemical recovery) were analyzed. Results 50 patients were included in the analysis, median age 34 (IQR 29-39) years, men significantly older than women, p=0.014. Most (92%) were female gender, and of black African ethnicity (86%). The median duration on ART at time of presentation was 6.5 months with half of the women initiating ART during pregnancy at a median gestation of 24 weeks (IQR 11 – 36). Median CD4 nadir at ART treatment initiation was 517 cells/mm3, with no significant difference (p=NS) in CD4 nadir in those pregnant or not. Median RUCAM score was 7 and of the 66% of patients who had liver biopsies, 3 histological patterns were identified: submassive necrosis (57,5%), nonspecific hepatitis (36%) and mixed cholestatic hepatitis (6%). Multivariate analysis suggested predictors for the development of submassive necrosis included age >30 years [OR 0.86 (0.15-0.97), p=0.02], pregnancy [OR 6.9 (1.34 – 35.6), p=0.02]; CD4 >350 [OR, 7.1 (1.5-31.9), p=0.02] but not alcohol use [OR 1.17 (0.72-1.18); p=0.07]. For the non-specific hepatitis group, only pregnancy predicted [OR 8.7 (1.3- 58.2), p=0.03]. The mortality rate was 14%, median time from admission to death was 15 days with the median duration to initial hospital discharge 33 (IQR 24 -52) days. Biochemical recovery was prolonged necessitating a follow up period of more than a year at an outpatient specialist clinic. 86% initiated protease inhibitor based ART successfully. Conclusion EFV DILI is a severe injury with significant inpatient mortality and morbidity requiring prolonged hospitalization and outpatient follow up.