James J. Pomposelli

Infusion of tumor necrosis factor/cachectin promotes muscle catabolism in the rat. A synergistic effect with interleukin 1.

To improve our understanding of the metabolic role of cytokines in protein wasting, we estimated the rates of protein synthesis and degradation in muscle and liver tissues in intact rats treated with several doses of recombinant IL 1 and/or tumor necrosis factor (TNF)/cachectin. Protein breakdown in muscle and liver were derived in vivo from the relationship between [14C]leucine distribution and tissue dilution in reference to circulating leucine. Synthesis was derived from the relationship between [14C]leucine appearance in the protein-bound and free-tissue leucine pools. To specifically relate changes in leucine tracer metabolism to protein dynamics, we separately measured the effect of these cytokines on blood flow to different tissues. The increase in dilution of the tissue-free [14C]leucine by TNF and TNF/IL 1 mixture, but not by IL 1 alone, could not be explained by a hemodynamic effect of these cytokines. Rather, this finding indicated that muscle proteolysis is enhanced by TNF and synergistically augmented by the addition of IL 1. Compatible with these data was the finding that more prolonged infusions of recombinant TNF/cachectin and the combination with IL 1 increased urinary nitrogen excretion. Changes in [14C]leucine dilution in the liver were less pronounced than those in skeletal muscle and consistent with net anabolic effect of TNF on liver protein. We conclude that rats exposed systemically to sublethal doses of TNF respond with increasing muscle and decreasing liver proteolysis, similar to that observed in inflammation and in cancer.

Liver regeneration and surgical outcome in donors of right-lobe liver grafts.

Introduction. Previous studies of healthy live‐liver donors have suggested that complete liver regeneration occurs within a matter of weeks; however, there have been no long‐term studies evaluating liver regeneration and few studies documenting long‐term donor outcome. Materials and Methods. Fifty‐one donors who provided right‐lobe grafts underwent volumetric spiral computed tomography scans preoperatively and postoperatively at time intervals of 1 week and 1, 3, 6, and 12 months. Patient demographics, surgical data, and postoperative outcome were correlated with liver regeneration data. Donor surgical outcome was followed prospectively and recorded in a comprehensive database. Results. Thirty‐three males and 18 females (mean age 36.0±9.6 years) provided 51 right‐lobe grafts. Mean follow‐up was 9.8±3.4 months. No donor operation was aborted, and surgical morbidity and mortality rates were 39% and 0%, respectively. Donor remnant liver volume was 49.4±5.7% of the original total liver volume (TLV). Overall liver regeneration was 83.3±9.0% of the TLV by 1 year. Female donors had significantly slower liver regrowth when compared with males at 12 months (79.8±9.3% vs. 85.6±8.2%, P<0.01). There was no effect of age, body mass index, operative time, estimated blood loss, postoperative complications, or perioperative liver function tests on liver regeneration. Discussion. Liver regeneration continues throughout the first postoperative year. Only one donor achieved complete liver regeneration during this time period; however, all donors have maintained normal liver function without long‐term complications. Longer follow‐up is needed to determine whether donors ever achieve original TLV.

Incidence of death and potentially life‐threatening near‐miss events in living donor hepatic lobectomy: A world‐wide survey

The incidence of morbidity and mortality after living donor liver transplantation (LDLT) is not well understood because reporting is not standardized and relies on single‐center reports. Aborted hepatectomies (AHs) and potentially life‐threatening near‐miss events (during which a donors life may be in danger but after which there are no long‐term sequelae) are rarely reported. We conducted a worldwide survey of programs performing LDLT to determine the incidence of these events. A survey instrument was sent to 148 programs performing LDLT. The programs were asked to provide donor demographics, case volumes, and information about graft types, operative morbidity and mortality, near‐miss events, and AHs. Seventy‐one programs (48%), which performed donor hepatectomy 11,553 times and represented 21 countries, completed the survey. The average donor morbidity rate was 24%, with 5 donors (0.04%) requiring transplantation. The donor mortality rate was 0.2% (23/11,553), with the majority of deaths occurring within 60 days, and all but 4 deaths were related to the donation surgery. The incidences of near‐miss events and AH were 1.1% and 1.2%, respectively. Program experience did not affect the incidence of donor morbidity or mortality, but near‐miss events and AH were more likely in low‐volume programs (≤50 LDLT procedures). In conclusion, it appears that independently of program experience, there is a consistent donor mortality rate of 0.2% associated with LDLT donor procedures, yet increased experience is associated with lower rates of AH and near‐miss events. Potentially life‐threatening near‐miss events and AH are underappreciated complications that must be discussed as part of the informed consent process with any potential living liver donor. Liver Transpl 19:499–506, 2013.

Role of biochemical mediators in clinical nutrition and surgical metabolism

Over the past several decades, research on the role of mediators in inflammation, immunity, repair processes, cell growth, and substrate metabolism have centered around the use of purified products of stimulated macrophages. With the current availability of recombinant mediators, the participation of individual monokines in cellular metabolism has been more clearly defined. Interactions among various mediators have been demonstrated, but their exact role in metabolism is currently under intense study. With the use of recombinant monokines, formal evidence for their participation in the acute phase response has been developed. Their use has also assisted in the reinterpretation of data gathered in older studies using purified preparations, which were almost certainly contaminated with several monokines. In this review we will try to give the reader insight into recent advances in the understanding of the role of cellular mediators in relation to nutrition and intermediary metabolism. With a clearer knowledge of the role of cellular mediators in the pathophysiology of disease, it may be possible to develop rationales for their therapeutic use as modulators of substrate metabolism during critical illness.

Living donor adult liver transplantation: a longitudinal study of the donor's quality of life.

We report the results of a prospective, longitudinal quality of life survey on our adult right lobe (RL) liver donors. A total of 47 donors were enrolled; a standard SF‐36 form and 43 questions developed by our team were completed before donation, at 1 week, and 1, 3, 6 and 12 months after donation. There were no donor deaths. Twenty‐nine complications occurred in 16 patients. Major complication rate was 12.8%. Employment status and personal finances were identified as major stressors. All donors who wished to return to work did so by 1 year (mean 3.4 months). Individuals reported between

Living donor liver transplantation for hepatocellular carcinoma: Increased recurrence but improved survival.

0 and

Donor postextubation hypotension and age correlate with outcome after donation after cardiac death transplantation.

25 000 in losses (wages, travel, lodging, etc.). Relationships with recipients and other family members were not altered significantly. Anticipated pain (predonation) was greater than actual pain reported. Donors indicated satisfaction with the donation process regardless of recipient outcome. Physical complaints were significant at 1 week and 1 month, but returned to baseline. Donor mental health remained stable. In conclusion, RL donors found the experience to be a positive one throughout the first postdonation year. The study identified areas (finances, employment and expected recipient outcomes) to be stressed as future donors are evaluated.

Enriched Branched-Chain Amino Acid Formula Versus a Casein-Based Supplement in the Treatment of Cirrhosis

In regions with a limited deceased donor pool, living donor adult liver transplantation (LDALT) has become an important treatment modality for patients with hepatocellular carcinoma (HCC) and cirrhosis. Studies have shown higher recurrence rates of HCC after LDALT in comparison with deceased donor liver transplantation (DDLT). The aim of our study was to examine the outcome results and recurrence rates for patients with HCC who underwent LDALT at our center. During an 8‐year period, 139 patients underwent LDALT, of whom 28 (20.1%) had HCC in their explanted livers. The median follow‐up was 40.8 months. The mean explant tumor size was 3.3 ± 1.2, and the mean number of tumors was 1.5 ± 0.8. Twenty‐one patients (75%) had tumors within the Milan criteria, 5 patients had tumors outside the Milan criteria but within the University of California San Francisco (UCSF) criteria, and 2 patients were beyond the UCSF criteria. The overall 1‐ and 5‐year patient and graft survival rates were 96% and 81%, respectively. Survival following LDALT was significantly better than survival following DDLT for HCC during the same time period (P = 0.02). Eight patients (28.6%) developed tumor recurrence. Poor differentiation of tumor cells was the most significant determinant of recurrence. Despite high recurrence rates of HCC following LDALT, overall 5‐year survival appears to be excellent. Liver Transpl 15:1861–1866, 2009.

Human monoclonal antibody MBL-HCV1 delays HCV viral rebound following liver transplantation: a randomized controlled study.

Background. Compared with standard donors, kidneys recovered from donors after cardiac death (DCD) exhibit higher rates of delayed graft function (DGF), and DCD livers demonstrate higher rates of biliary ischemia, graft loss, and worse patient survival. Current practice limits the use of these organs based on time from donor extubation to asystole, but data to support this is incomplete. We hypothesized that donor postextubation parameters, including duration and severity of hemodynamic instability or hypoxia might be a better predictor of subsequent graft function. Methods. We performed a retrospective examination of the New England Organ Bank DCD database, concentrating on donor factors including vital signs after withdrawal of support. Results. Prolonged, severe hypotension in the postextubation period was a better predictor of subsequent organ function that time from extubation to asystole. For DCD kidneys, this manifested as a trend toward increased DGF. For DCD livers, this manifested as increased rates of poor outcomes. Maximizing the predictive value of this test in the liver cohort suggested that greater than 15 min between the time when the donor systolic blood pressure drops below 50 mm Hg and flush correlates with increased rates of diffuse biliary ischemia, graft loss, or death. Donor age also correlated with worse outcome. Conclusions. Time between profound instability and cold perfusion is a better predictor of outcome than time from extubation to asystole. If validated, this information could be used to predict DGF after DCD renal transplant and improve outcomes after DCD liver transplant.

Improved Survival After Live Donor Adult Liver Transplantation (LDALT) Using Right Lobe Grafts: Program Experience and Lessons Learned

An orally administered branched-chain amino acid (BCAA) rich supplement (T), Travasorb-Hepatic was compared to a casein based supplement (E), Ensure, in a randomized double-blind cross-over study in eight malnourished, stable cirrhotics unable to achieve a daily dietary protein intake of 1.0 g/kg. Doses of antiportal systemic encephalopathy drugs remained constant and a baseline 1000 kcal, 40 g dietary protein intake was encouraged. To this diet, supplemental protein was added in daily 20-g increments to a maximum of 60 g supplemental protein. Mental status, asterixis, and number connection tests were assessed daily and an antiportal systemic encephalopathy index calculated. There was no significant difference in the mean intake of dietary protein (T, 33.7 +/- 4.0 g; E, 26.7 +/- 10.8 g), supplemental protein (T, 43.1 +/- 8.3 g; E, 47.9 +/- 7.1 g), or N2 balance (T, 4.2 +/- 3.7 g; E, 3.4 +/- 4.4) between treatment trials. The antiportal systemic encephalopathy index improved on E, with no significant change in the BCAA:aromatic acid molar ratio. This ratio improved on T (1.02 +/- 2.0 to 2.7 +/- 1.1), but was not accompanied by improvement in the antiportal systemic encephalopathy index. The improved protein tolerance in both groups was not further increased by a highly enriched BCAA formula compared to one with a moderate BCAA content from a natural dietary protein source. Thus, both conventional casein-based supplements and enriched BCAA formulas are well tolerated and can be safely and effectively used as an integral part of diet therapy.