Heidi Yeh - Academia.edu (original) (raw)

Papers by Heidi Yeh

Frontiers in Physics, Dec 22, 2022

Introduction: The current liver organ shortage has pushed the field of transplantation to develop... more Introduction: The current liver organ shortage has pushed the field of transplantation to develop new methods to prolong the preservation time of livers from the current clinical standard of static cold storage. Our approach, termed partial freezing, aims to induce a thermodynamically stable frozen state at high subzero storage temperatures (−10°C to −15°C), while simultaneously maintaining a sufficient unfrozen fraction to limit ice-mediated injury. Methods and results: Using glycerol as the main permeating cryoprotectant agent, this research first demonstrated that partially frozen rat livers showed similar outcomes after thawing from either −10°C or −15°C with respect to subnormothermic machine perfusion metrics. Next, we assessed the effect of adding ice modulators, including antifreeze glycoprotein (AFGP) or a polyvinyl alcohol/polyglycerol combination (X/Z-1000), on the viability and structural integrity of partially frozen rat livers compared to glycerol-only control livers. Results showed that AFGP livers had high levels of ATP and the least edema but suffered from significant endothelial cell damage. X/Z-1000 livers had the

Pediatric Transplantation, Mar 5, 2017

Primary hyperoxaluria type 1 (PH1) is a rare liver enzymatic defect that causes overproduction of... more Primary hyperoxaluria type 1 (PH1) is a rare liver enzymatic defect that causes overproduction of plasma oxalate. Accumulation of oxalate in the kidney and subsequent renal failure are fatal to PH1 patients often in pediatric age. Combined liver and kidney transplantation is the therapy of choice for end-stage renal disease due to PH1. Levels How to cite this article: Villani V, Gupta N, Elias N, et al. Bilateral native nephrectomy reduces systemic oxalate level after combined liver-kidney transplant: A case report.

Pediatric Transplantation, Nov 1, 2016

The distance to liver transplant centers affects outcomes in adult liver transplantation. Because... more The distance to liver transplant centers affects outcomes in adult liver transplantation. Because pediatric patients are particularly vulnerable, we hypothesized that distance adversely affects the time to transplantation and waitlist mortality. The SRTR was queried for isolated pediatric liver transplant registrants (under age 18) with valid ZIP code information from 2003 to 2012. Distance was measured from home ZIP code to listing transplant center. Competing events analysis, adjusted for demographic factors, indication, and PELD, was undertaken for transplantation and death while on the waitlist. The median distance to listing transplant center for 6924 children was 65 (IQR 17.5-189) miles. Median distance traveled increased by listing volume (73.9 vs 33.8 miles, highest vs lowest volume quartile, P<.001 for trend) and varied across the country. Longer distance was not associated with time to transplantation (HR 0.99, longest vs shortest distance quartile, P=.80), but was associated with increased mortality (HR 1.75, P<.001). Larger centers attract patients from a distance, while smaller centers serve local populations. Increasing distance is associated with a higher risk of waitlist death, which may reflect decreased access to specialist and tertiary care associated with a transplant center.

Transplantation, Sep 27, 2011

Nature Biomedical Engineering, Nov 30, 2020

Transplantation, Sep 1, 2022

Transplantation, Feb 1, 2020

Background: Delisting for being "too sick" to be transplanted is subjective. Previous work has de... more Background: Delisting for being "too sick" to be transplanted is subjective. Previous work has demonstrated the mortality of patients delisted for "too sick" is unexpectedly low. Transplant centers use their best clinical judgment for determining "too sick", but it is unclear how social determinants influence decisions to delist for "too sick". We hypothesized social determinants and Donor Service Area (DSA) characteristics may be associated with determination of "too sick" to transplant. Methods: Data were obtained from the Scientific Registry of Transplant Recipients for adults listed and removed from the liver transplant waitlist from 2002 to 2017. Patients were included if delisted for "too sick". Our primary outcome was Model for End Stage Liver Disease (MELD) score at waitlist removal for "too sick". Regression assessed the association between social determinants and MELD at removal for "too sick". Results: We included 5,250 delisted for "too sick" at 127 centers, in 53 DSAs, over 16 years. The mean MELD at delisting for "too sick" was 25.8 (SD +/-11.2). On adjusted analysis, social determinants including age, race, gender, and education predicted the MELD at delisting for "too sick" (p<0.05). Conclusions: There is variation in delisting MELD for "too sick" score across DSA and time. While social determinants at the patient and system level are associated with delisting practices, the interplay of these variables warrants additional research. In addition, center outcome reports should include waitlist removal rate for "too sick" and waitlist death ratios, so waitlist management practice at individual centers can be monitored.

Current Opinion in Organ Transplantation, Jun 1, 2008

Purpose of review Because the gap between liver organ supply and demand continues to increase, ad... more Purpose of review Because the gap between liver organ supply and demand continues to increase, adult living-donor liver transplantation continues to represent a significant pool of organs. Recent findings With this in mind, we discuss recent issues in adult living-donor liver transplantation, including issues with donor evaluation and selection, donor liver biopsy, orphan organ allocation, donor morbidity and mortality, outcomes compared with deceased donor liver transplant from time of evaluation, death on the waiting list, and evolving recipient indications for living-donor liver transplantation. Summary Increasing the number of living-donor liver transplants would allow us to expedite transplant, avoid death on the waitlist, and possibly save more lives by expanding the criteria for transplant. These benefits must always be weighed against the potential risks and complications to the donor, which can be significant.

Frontiers in Surgery, Jun 17, 2021

Background: A major limitation in expanding the use of donation after circulatory death (DCD) liv... more Background: A major limitation in expanding the use of donation after circulatory death (DCD) livers in transplantation is the increased risk of graft failure secondary to ischemic cholangiopathy. Warm ischemia causes thrombosis and injury to the peribiliary vascular plexus (PVP), which is supplied by branches of the hepatic artery, causing higher rates of biliary complications in DCD allografts. Aims/Objectives: We aimed to recondition discarded DCD livers with tissue plasminogen activator (tPA) while on normothermic machine perfusion (NMP) to improve PVP blood flow and reduce biliary injury. Methods: Five discarded DCD human livers underwent 12 h of NMP. Plasminogen was circulated in the base perfusate prior to initiation of perfusion and 1 mg/kg of tPA was administered through the hepatic artery at T = 0.5 h. Two livers were split prior to perfusion (S1, S2), with tPA administered in one lobe, while the other served as a control. The remaining three whole livers (W1-W3) were compared to seven DCD control liver perfusions (C1-C7) with similar hepatocellular and biliary viability criteria. D-dimer levels were measured at T = 1 h to verify efficacy of tPA. Lactate, total bile production, bile pH, and difference in biliary injury scores before and after perfusion were compared between tPA and non-tPA groups using unpaired, Mann-Whitney tests. Results: Average weight-adjusted D-dimer levels were higher in tPA livers in the split and whole-liver model, verifying drug function. There were no differences in perfusion hepatic artery resistance, portal vein resistance, and arterial lactate between tPA livers and non-tPA livers in both the split and whole-liver model. However, when comparing biliary injury between hepatocellular and biliary non-viable whole livers, tPA livers had significantly lower PVP injury scores (0.67 vs. 2.0) and mural stroma (MS) injury scores (1.3 vs. 2.7). Conclusion: This study demonstrates that administration of tPA into DCD livers during NMP can reduce PVP and MS injury. Further studies are necessary to assess the effect of tPA administration on long term biliary complications.

Transplantation, Jun 27, 2008

Background. Expanded regional sharing of liver allografts may increase cold ischemia and allograf... more Background. Expanded regional sharing of liver allografts may increase cold ischemia and allograft failure, particularly with livers from older donors. The aim of this study was to examine whether older donor age and cold ischemic time interact to produce inferior allograft survival. Methods. We undertook a retrospective cohort study of adult liver transplants in the United States performed between December 1, 1995 and December 31, 2005, using data from the Organ Procurement and Transplantation Network. The primary outcome was allograft failure within 90 days. Results. Forty-four thousand seven hundred fifty-six liver transplant recipients were analyzed. Older age was defined as 45 years or more, and prolonged cold ischemia was defined as 12 hours or more. Using data from the pre-Model for End Stage Liver Disease (MELD), post-MELD and combined eras, three separate analyses of the interaction between older donor age and prolonged cold ischemia were performed. In multivariable logistic regression, the interaction of age 45 years or more and cold ischemia more than or equal to 12 hr reached statistical significance in the combined (OR 1.24, CI 1.08-1.42, PϽ0.01) and pre-MELD (OR 1.26, CI 1.08-1.46, PϽ0.01) datasets, but not in the smaller post-MELD dataset (OR 1.18, CI 0.81-1.72, Pϭ0.38). In the combined dataset, recipients of livers from donors aged 45 years or more and cold ischemia more than or equal to 12 hr showed an adjusted absolute risk of allograft failure at 90 days of 17.3% (odds ratio 1.84), compared with 11.1% for recipients of livers from donors older than 45 years and cold ischemia less than 12 hr. Conclusions. These findings suggest that older donor age and prolonged cold ischemia interact to increase liver allograft failure at 90 days. Proposals to expand regional sharing of older livers should be regarded with caution.

Annals of Surgery, Aug 15, 2023

Objective: To assess how liver allografts preserved using portable normothermic machine perfusion... more Objective: To assess how liver allografts preserved using portable normothermic machine perfusion (NMP) compare against those that underwent ischemic cold storage (ICS) in the setting of donation after brain death (DBD) and donation after circulatory death (DCD) liver transplantation (LT). Background: Compared with conventional ICS, NMP may offer more homeostatic preservation, permit physiological assessment of organ function, and provide opportunities for graft improvement/modification. We report a single-center US experience of liver NMP. Methods: A single-center, retrospective analysis of collected data on 541 adult whole LTs from 469 DBD donors [NMP (n = 58) vs ICS (n = 411)] and 72 DCD donors [NMP (n = 52) vs ICS (n = 20)] between January 2016 and December 2022. Results: In DBD LT, male sex [odds ratio (95% CI): 1.83 (1.08–3.09)] and >10% macrosteatosis of the donor liver [1.85 (1.10–3.10)] were statistically significant independent risk factors of early allograft dysfunction (EAD). Donor age >40 years and cold ischemia time >7 hours were independent risk factors of reperfusion syndrome (RPS). One-year, 3-year, and 5-year incidences of ischemic cholangiopathy (IC) did not differ significantly in DBD cases between the NMP and ICS cohorts. In DCD LT, NMP was an independent protective factor against EAD [0.11 (0.03–0.46)] and RPS [0.04 (0.01–0.25)]. The incidence of IC in the DCD cases at 1-year and 3-year time points was significantly lower in the NMP cohort (1.9% compared with 20% in the ICS group). Conclusions: Compared with conventional ICS, NMP can significantly reduce the incidence of EAD, RPS, and IC after DCD LT.

Transplantation, Nov 1, 2012

John Wiley & Sons, Ltd eBooks, Jul 25, 2014

Deoxyguanosine kinase (DGUOK) deficiency is a well-known cause of hepatocerebral mitochondrial DN... more Deoxyguanosine kinase (DGUOK) deficiency is a well-known cause of hepatocerebral mitochondrial DNA depletion syndromes, which include a broad spectrum of clinical presentations. Affected patients often develop life-threatening liver failure, but the benefits of liver transplantation (LT) are controversial because of the frequently severe neurological involvement due to the underlying mitochondrial disease. We describe the long-term clinical course of 2 patients from our institution and provide an update on their outcomes after LT with this condition. Another 12 pediatric patients were identified through a systematic search of the literature. All 14 reported patients underwent transplantation in infancy despite mild to moderate neurological impairment in some cases. The 2 DGUOK-deficient patients from our center displayed liver failure and mild to moderate neurological involvement. At the time of this writing, they had been followed for 5 and 8 years after LT, both patients were alive, and they had only mild neurological symptoms. Three of the 12 patients identified through the literature review survived for a long time (17, 12, and 23 years); 8 died during early follow-up; and for 1 patient, no follow-up information was available. The 1-year survival rate was 64%; 36% survived for more than 5 years. The long-term survivors had good quality of life. In conclusion, although survival after LT for DGUOK deficiency is lower than survival after LT for other indications, a significant proportion of patients benefit from LT with long-term survival and a stable neurological situation despite initial neurological abnormalities. Nevertheless, a decision to carry out LT for patients with DGUOK deficiency remains difficult because neurological symptoms may occur and worsen after LT despite their absence before transplantation.

Transplantation direct, Mar 1, 2019

Von Meyenburg complexes, or multiple biliary hamartomas, are often asymptomatic lesions incidenta... more Von Meyenburg complexes, or multiple biliary hamartomas, are often asymptomatic lesions incidentally discovered during abdominal or hepatic imaging. The presentation of clinically significant Von Meyenburg complexes ranges from cholestasis and self-limited episodes of cholangitis to malignant degeneration into cholangiocarcinoma. In cases of persistent or recurrent cholangitis, treatment is a significant challenge. Definitive source control with liver transplantation, as in other cases of cholestatic liver disease, may be necessary.

Scientific Reports, Nov 30, 2021

In transplantation, livers are transported to recipients using static cold storage (SCS), whereby... more In transplantation, livers are transported to recipients using static cold storage (SCS), whereby livers are exposed to cold ischemic injury that contribute to post-transplant risk factors. We hypothesized that flushing organs during procurement with cold preservation solutions could influence the number of donor blood cells retained in the allograft thereby exacerbating cold ischemic injury. We present the results of rat livers that underwent 24 h SCS after being flushed with a cold University of Wisconsin (UW) solution versus room temperature (RT) lactated ringers (LR) solution. These results were compared to livers that were not flushed prior to SCS and thoroughly flushed livers without SCS. We used viability and injury metrics collected during normothermic machine perfusion (NMP) and the number of retained peripheral cells (RPCs) measured by histology to compare outcomes. Compared to the cold UW flush group, livers flushed with RT LR had lower resistance, lactate, AST, and ALT at 6 h of NMP. The number of RPCs also had significant positive correlations with resistance, lactate, and potassium levels and a negative correlation with energy charge. In conclusion, livers exposed to cold UW flush prior to SCS appear to perform worse during NMP, compared to RT LR flush. In the United States, the demand for transplantable livers far outstrips supply, with over 12,000 patients on the waitlist for a liver transplant but less than 9000 transplants done annually 1,2. One challenge in liver transplantation that contributes to this organ shortage is damage to the liver graft during transportation using static cold storage (SCS). Cold ischemic time (CIT) of a liver graft is defined as the interval between in situ cold preservation flush of the organ during procurement to removal of the graft from 4 °C SCS at time of implantation 3. Cold ischemia is a known driver of ischemia reperfusion injury as the liver transitions from oxygen limiting conditions at 4 °C to higher metabolic rates at normothermic temperatures during implantation. Longer CITs have been shown to lead to higher rates of early allograft dysfunction 4 and primary nonfunction 5. Despite the success of SCS in organ transportation, more work is required to fully uncover the mechanisms of cold ischemic injury on the liver, and the impact of methods that prepare the liver allograft for SCS remain understudied. During clinical organ procurement, the donor liver is perfused in situ through the aorta and portal vein (PV) using cold (4 °C) University of Wisconsin (UW) solution. Once the donor hepatectomy is complete, retained blood in the liver is flushed out using additional UW solution on the back table until clear fluid emerges from the inferior vena cava (IVC) 6. The temperature, composition, and viscosity of flushing solution has been shown to be an important determination of liver graft function after transplant 7,8. However, even after cold flushing, donor blood remains in the liver allograft, which may be harmful to resident cells, especially during SCS. Platelets, neutrophils, and red blood cells (RBCs) are well known to be affected by thermal stresses. For example, hypothermic conditions promote platelet activation and aggregation by changing platelet shape, increasing

Transplantation, Jul 1, 2014

cellular damage was signifi cantly lower, and the levels of TNFα and IL-1β were higher in both th... more cellular damage was signifi cantly lower, and the levels of TNFα and IL-1β were higher in both the SOWP and SOWP+PG groups. Bile production and liver ATP levels were increased, and malondialdehyde levels were decreased in the SOWP+PG group, compared to NT group. CONCLUSION: These results indicate the benefi cial effects of performing SOWP before cold preservation and the additional effects of PGE1 to SOWP, which may also be useful in human LTx involving NHBDs.

Transplantation direct, Aug 4, 2022

American Journal of Transplantation, Nov 1, 2017

Transplantation, Mar 1, 2019

Original Clinical Science-Liver Background. Getting listed for liver transplantation is a complex... more Original Clinical Science-Liver Background. Getting listed for liver transplantation is a complex process. Institutional health literacy may influence the ability of patients with limited educational attainment (EA) to list. As an easily accessible indicator of institutional health literacy, we measured the understandability of liver transplant center education websites and assessed whether there was any association with the percentage of low EA patients on their waitlists. Methods. Patients on the waitlist for liver transplantation 2007-2016 were identified in Scientific Registry of Transplant Recipients. Understandability of patient education websites was assessed using the Clear Communication Index (CCI). The Centers for Disease Control and Prevention has set itself a goal CCI of 90 as being easy to understand. Low EA was defined as less than a high school education. We adjusted for center case-mix, Donor Service Area characteristics, and EA of the general population. Results. Patients (84 774) were listed across 112 liver transplant centers. The median percent of waitlisted patients at each center with low EA was 11.0% (IQR, 6.6-16.8). CCI ranged from 53 to 88 and correlated with the proportion of low EA patients on the waitlist. However, CCI was not associated with the percentage of low EA in the general population. For every 1-point improvement in CCI, low EA patients increase by 0.2% (P < 0.05), translating to a 3.6% increase, or additional 3000 patients, if all centers improved their websites to CCI of 90. Conclusions. Educational websites that are easier to understand are associated with increased access to liver transplantation for patients with low EA. Lowering the health literacy burden by transplant centers may improve access to the liver transplant waitlist.

Frontiers in Immunology

Access to liver transplantation is limited by a significant organ shortage. The recent introducti... more Access to liver transplantation is limited by a significant organ shortage. The recent introduction of machine perfusion technology allows surgeons to monitor and assess ex situ liver function prior to transplantation. However, many donated organs are of inadequate quality for transplant, though opportunities exist to rehabilitate organ function with adjunct therapeutics during normothermic machine perfusion. In this preclinical study, we targeted the apoptosis pathway as a potential method of improving hepatocellular function. Treatment of discarded human livers during normothermic perfusion with an irreversible pan-caspase inhibitor, emricasan, resulted in significant mitigation of innate immune and pro-inflammatory responses at both the transcriptional and protein level. This was evidenced by significantly decreased circulating levels of the pro-inflammatory cytokines, interleukin-6, interleukin-8, and interferon-gamma, compared to control livers. Compared to emricasan-treated li...