Bile formation in long-term ex situ perfused livers

Eshmuminov, Dilmurodjon; Schüler, Martin; Becker, Dustin; Borrego, Lucía Bautista; Mueller, Matteo; Hagedorn, Catherine; Häusler, Stéphanie; Steiger, Julia; Tibbitt, Mark W.; Dutkowski, Philipp; Rohr, Philipp Rudolf von; Stieger, Bruno; Hefti, Max; Clavien, Pierre‐Alain

doi:10.1016/j.surg.2020.11.042

Cited by 13 publications

(15 citation statements)

References 40 publications

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“…The authors concluded that GGT might be predictive of livers that are at risk of developing cholangiopathies ( 34 ). A long-term perfusion protocol for 7-day NMP was established by Eshmuminov et al ( 36 ). The authors included 23 porcine livers of which 3 were transplanted.…”

Section: Biliary Assessment During Nmpmentioning

confidence: 99%

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Biliary Viability Assessment and Treatment Options of Biliary Injury During Normothermic Liver Perfusion—A Systematic Review

Dingfelder¹,

Rauter²,

Berlakovich³

et al. 2022

Transpl Int

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In recent years, significant progress has been made in the field of liver machine perfusion. Many large transplant centers have implemented machine perfusion strategies in their clinical routine. Normothermic machine perfusion (NMP) is primarily used to determine the quality of extended criteria donor (ECD) organs and for logistical reasons. The vast majority of studies, which assessed the viability of perfused grafts, focused on hepatocellular injury. However, biliary complications are still a leading cause of post-transplant morbidity and the need for re-transplantation. To evaluate the extent of biliary injury during NMP, reliable criteria that consider cholangiocellular damage are needed. In this review, different approaches to assess damage to the biliary tree and the current literature on the possible effects of NMP on the biliary system and biliary injury have been summarized. Additionally, it provides an overview of novel biomarkers and therapeutic strategies that are currently being investigated. Although expectations of NMP to adequately assess biliary injury are high, scant literature is available. There are several biomarkers that can be measured in bile that have been associated with outcomes after transplantation, mainly including pH and electrolytes. However, proper validation of those and other novel markers and investigation of the pathophysiological effect of NMP on the biliary tree is still warranted.

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Section: Biliary Assessment During Nmpmentioning

confidence: 99%

“…B/p glucose ratio <0.7 was met by all porcine livers and the viable human livers. To use bile flow as a reliable viability criterion it should be complemented with bile composition parameters ( 36 ).…”

Section: Biliary Assessment During Nmpmentioning

confidence: 99%

Biliary Viability Assessment and Treatment Options of Biliary Injury During Normothermic Liver Perfusion—A Systematic Review

Dingfelder¹,

Rauter²,

Berlakovich³

et al. 2022

Transpl Int

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“…Bile, comprising mainly BAs, cholesterol, bilirubin, bile pigment, phosphatidylcholine, water and inorganic salts, plays crucial roles in the digestion and absorption of lipids and lipid-soluble drugs. Bile production begins at the canaliculus in hepatocytes, and bile is modified downstream by cholangiocytes [18,19]. Bile formation is a fundamental physiological process comprising the active transport of BAs and other solutes across the canalicular membrane [20].…”

Section: Physiology Of Hepatobiliary Transport and Bile Formationmentioning

confidence: 99%

Molecular mechanisms of transporter regulation and their impairment in intrahepatic cholestasis

et al. 2022

Acta Materia Medica

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Intrahepatic cholestasis (IC) is a liver disease caused by disorders in bile formation and excretion, owing to structural and functional abnormalities in hepatocytes and/or bile capillaries. IC is commonly caused by hepatitis virus, alcohol consumption, drug-induced liver damage, autoimmune liver disease and heredity. In the absence of effective treatment, IC can progress to liver fibrosis, cirrhosis and ultimately liver failure. However, the mechanisms underlying IC remain poorly understood. IC is believed to be closely associated with changes in the transcription, function and localization of hepatocellular transport proteins. To better understand the molecular mechanisms of transport proteins in IC, herein, we review the roles of these transport proteins and discuss their underlying regulatory mechanisms in IC. Our aim is to provide a reference for understanding IC pathogenesis and developing effective drug therapies.

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“…1,4 We recently introduced a unique liver perfusion technology that maintains human livers viable and in a metabolically active state for up to one week (Figure 1). 4,[9][10][11][12][13] With this device, it is possible to perfuse and observe/assess livers prior transplantation at close to physiological conditions for up to one week.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of coagulation factors during long‐term ex situ liver perfusion

et al. 2021

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Robust viability assessment of grafts during normothermic liver perfusion is a prerequisite for organ use. Coagulation parameters are used commonly for liver assessment in patients. However, they are not yet included in viability assessment during ex situ perfusion. In this study, we analysed coagulation parameters during one week ex situ perfusion at 34℃. Eight discarded human livers were perfused with bloodbased, heparinised perfusate for one week; perfusions in a further four livers were terminated on day 4 due to massive ongoing cell death. Coagulation parameters were well below the physiologic range at perfusion start. Physiologic levels were achieved within the first two perfusion days for factor V (68.5 ± 35.5%), factor VII (83.5 ± 26.2%), fibrinogen (2.1 ± 0.4 g/L) and antithrombin (107 ± 26.5%) in the livers perfused for one week. Despite the increased production of coagulation factors, INR was detectable only at 24h of perfusion (2.1 ± 0.3) and prolonged thereafter (INR > 9). The prolongation of INR was related to the high heparin level in the perfusate (anti-FXa > 3 U/mL). Intriguingly, livers with ongoing massive cell death also disclosed synthesis of factor V and improved INR. In summary, perfused livers were able to produce coagulation factors at a physiological level ex situ. We propose that single coagulation factor analysis is more reliable for assessing the synthetic function of perfused livers as compared to INR when using a heparinised perfusate.

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Bile formation in long-term ex situ perfused livers

Cited by 13 publications

References 40 publications

Biliary Viability Assessment and Treatment Options of Biliary Injury During Normothermic Liver Perfusion—A Systematic Review

Biliary Viability Assessment and Treatment Options of Biliary Injury During Normothermic Liver Perfusion—A Systematic Review

Molecular mechanisms of transporter regulation and their impairment in intrahepatic cholestasis

Synthesis of coagulation factors during long‐term ex situ liver perfusion

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