Patricia A. Sheiner

Use of livers with microvesicular fat safely expands the donor pool

BACKGROUND The safety of transplanting livers with moderate to severe microvesicular steatosis is unknown. Livers that appear fatty are often abandoned at the donor hospital. We have recently used frozen-section biopsy to distinguish between microvesicular and macrovesicular steatosis. We present here our single-center experience with transplantation of 40 allografts with moderate or severe microvesicular steatosis. METHODS We reviewed our data on 426 transplants and identified 40 cases in which the donor liver contained at least 30% microvesicular steatosis. Early graft function, patient and graft survival, and donor risk factors for steatosis were examined, and results in this cohort were compared with results in all other patients who received liver transplants at our center during the same time period. We also analyzed the reliability of donor frozen-section biopsies in quantitating microsteatosis. Persistence of steatosis was assessed on the basis of 1-year follow-up biopsies. RESULTS The incidence of primary nonfunction and poor early graft function was 5% and 10%, respectively. One-year patient and graft survival rates were 80% and 72.5%, respectively. Donor obesity and traumatic death were commonly identified risk factors for microvesicular steatosis. Frozen-section biopsy was reliable for pretransplant decision-making about the use of potential grafts, and the steatosis had disappeared from the graft at 1 year in the majority of cases. CONCLUSIONS Livers with even severe microvesicular steatosis can be reliably used for transplantation without the fear of high rates of primary nonfunction. There was a significant incidence of poor early graft function, but this did not affect outcome. Microsteatosis is usually associated with some underlying risk factor in the donor and is reversible, as demonstrated by follow-up biopsies after transplant.

Safe use of hepatic allografts from donors older than 70 years

Between March 1991 and August 1995, 36 livers from donors >/=70 years old were transplanted. In donors, we recorded the following risk factors: alanine aminotransferase > 120 and rising, dopamine dose > 15 microg/kg/min, hypotension (systolic blood pressure <80) >1 hr, stay in the intensive care unit >5 days and body mass index >/=27. In 35 recipients, we recorded pretransplant United Network for Organ Sharing (UNOS) status, cold/warm ischemia time, intraoperative blood loss, and occurrence of poor early graft function or primary nonfunction. Mean recipient age was 55 years (range, 25-75 years). Four recipients were UNOS status 1, 19 were UNOS 2, and 12 were UNOS 3. Two livers were used as second grafts for primary graft nonfunction. Mean donor age was 73 years (range, 70-84 years). Intracranial bleeding was the cause of death in the majority of donors. The 36 donors had 40 risk factors; 10 donors had >1 risk factor. Mean cold and warm ischemia times were 9:08 +/- 2:57 hr and 51 +/- 9 min. Mean total operative time was 7.5 hr. Posttransplant mean peak alanine aminotransferase and aspartate aminotransferase levels were 937.3 +/- 703.1 IU/L and 923.3 +/- 708.5 IU/L, respectively. Mean prothrombin time on postoperative day 2 was 14.9 +/- 1.6 sec. Average total bilirubin on postoperative day 5 was 4.9 mg/dl. Median length of stay in the intensive care unit was 4 days. One recipient had poor early graft function; two recipients had primary nonfunction. Mean follow-up was 503 days (range, 110-1714 days). Three-month actual graft and patient survival rates were 85% and 91%, respectively. One-year actuarial graft and patient survival rates were also 85% and 91%, respectively. We conclude that older livers can be used safely. Advanced donor age should not be a contraindication to liver procurement.

Non‐adherence in pediatric liver transplant recipients − an assessment of risk factors and natural history

Abstract: Despite the fact that non‐adherence to medical therapy is one of the major causes of late morbidity and mortality in pediatric liver transplant recipients, little is known of the risk factors involved in this behavior. Three cases of fatal non‐adherence are reported. Factors associated with non‐adherence were investigated by performing a retrospective chart review of a panel of 27 variables in an age‐matched cohort of 15 pediatric liver transplant recipients. The most striking differences between the severely non‐adherent group and the age‐matched cohort included history of substance abuse, child abuse (physical or sexual), not having two parents at home, having received public assistance, having been diagnosed with a psychiatric disorder, and history of school dropout. In addition it appeared that a pretransplant diagnosis of autoimmune hepatitis was associated with more significant medical sequelae related to non‐adherence. These findings are preliminary owing to the retrospective design of this study, but could be used as a starting point for a prospective study of this important phenomenon.

An integrated approach to intestinal failure: results of a new program with total parenteral nutrition, bowel rehabilitation, and transplantation.

Intestinal failure can be treated with bowel rehabilitation, total parenteral nutrition, or intestinal transplantation. Little has been done to integrate these therapies for patients with intestinal insufficiency or failure and to develop an algorithm for appropriate use and timing. We established a multidisciplinary program using bowel rehabilitation, total parenteral nutrition, or intestinal transplantation as appropriate in a large population. Evaluation included clinical, pathlogic, and psychosocial assessments and assignment to therapy based on the results of this evaluation. Of 59 patients evaluated for life-threatening complications of intestinal failure, 68% were considered appropriate candidates for transplantation, 10% were managed with rehabilitation, and 17% were maintained on optimized long-term parenteral nutrition. Nineteen transplants were performed, with 78% patient survival and 66% graft survival. Patient survival among isolated intestine recipients was 90%. All patients managed with rehabilitation were weaned from parenteral nutrition within 6 months. Long-term management with parenteral nutrition resulted in a significant number of deaths both among patients waiting for a transplant and those who were poor candidates for transplant. Intestinal rehabilitation, when successful, is optimal. For patients with irreversible intestinal failure, isolated intestinal transplantation holds particular promise. Parenteral nutrition is plagued by high failure rates among this population of debilitated patients compared with the general parenteral nutrition population. Integration of these therapies, with individualization of care based on a multidisciplinary approach and perhaps with earlier isolated intestinal transplantation for patients with irreversible intestinal failure, should optimize survival.

The incidence and significance of late acute cellular rejection (>1000 days) after liver transplantation.

Abstract:  Acute cellular rejection (ACR) after liver transplantation occurs in as much as 70% of patients within the first year. There is very little known about ACR that occurs more than 1 yr after transplant, and it is generally believed that late occurring ACR may be more resistant to medical treatment and is associated with a higher rate of chronic ductopenic rejection and graft loss. A total of 532 recipients with more than 1000 d follow‐up and who did not have hepatitis C were identified. Forty‐three (8.1%) had biopsy proven late ACR at a mean of 1545 ± 441 d post‐transplant. Additionally, 38 of the 43 (88.4%) patients with late ACR had earlier episodes of ACR before 1000 d post‐transplant vs. only 295 of the 488 patients (60.5%) that did not have late ACR (p < 0.01). The incidence of primary sclerosing cholangitis (PSC) was 32.6% among patients with late ACR and 11.1% among patients without late ACR (p < 0.01). The overall patient survival for patients who had late ACR (n = 43) is 81.4% while for patients without late ACR (n = 488) it is 82.0% (p = ns). Patients remain at risk for ACR even after 1000 d post‐transplant, particularly those with PSC.

Correlation between von Willebrand factor levels and early graft function in clinical liver transplantation

Cold preservation/reperfusion leads to sinusoidal endothelial cell (SEC) activation and damage in nearly every liver transplantation; the extent of these changes influences early graft function. Upon reperfusion, activated SEC show increased expression of adhesion molecules, including von Willebrand factor (vWF) which is released into the circulation. This study was designed to evaluate the levels of vWF measured in the caval effluent and correlate these findings with known markers of SEC damage and early graft function. Data were obtained from 35 patients undergoing orthotopic liver transplantation (LTx). Two samples were taken from each patient for measurement of vWF: a) from the portal vein immediately prior to reperfusion; and b) from the first 50 ml of the caval effluent. Commercial assays were used to measure vWF, as well as hyaluronic acid (HA), thrombomodulin (TM), IL‐1β, IL‐6, IL‐8 and TNF‐α. Patients were divided into two groups based on early graft function. Poor early graft function (PEGF) was defined as a peak aspartate transaminase (AST) or alanine transaminase (ALT) level> 2500 U/L during the first three postoperative days (POD) and a prothrombin time (PT)> 16 s on POD 2 (n=8). The remaining 27 patients had good early graft function (GEGF). In patients with GEGF, vWF levels dropped significantly between the two time points. This change was not observed in those with PEGF. A positive linear correlation was observed in the PEGF group between vWF and HA and IL‐6. The different pattern of change in vWF between the two groups, as well as the positive correlation between HA, IL‐6 and vWF in PEGF, suggest that vWF may be a useful marker of early graft function.

Th1/Th2 cytokines and ICAM–1 levels post-liver transplant do not predict early rejection

Th1 derived cytokines IFN-gamma and IL-2, Th2 cytokine IL-4, and ICAM-1 have been implicated in liver allograft rejection. In order to determine whether monitoring of cytokine profiles during the first days post-liver transplant can predict early rejection we measured IFN-gg, IL-2, sIL-2 receptor, IL-4 and ICAM-1 in 22 patients, in plasma samples obtained within 4 h after liver perfusion (baseline) and between postoperative days (POD) 3-6. ICAM-1 and sIL-2R levels at POD 3-6 were significantly higher than at baseline but did not differ in presence or absence of rejection. Mean percentage increase of ICAM-1 levels was significantly lower in patients with Muromonab-C3 Orthoclone OKT3 (J.C. Health Care) (OKT3) whereas percentage increase of sIL-2R levels was higher in OKT3-treated patients. IFN-gamma levels at POD 3-6 increased from baseline while IL-4 levels were unchanged. Levels of IFN-gamma, IL-4 and their ratios did not correlate with rejection or immunosuppressive therapy. Thus, Th1/Th2 cytokine monitoring during the first week post-transplant does not predict early rejection and immunosuppressive therapy is the predominant factor affecting ICAM and sIL-2R levels after liver transplantation.

Recurrence of hepatitis C after liver transplantation is associated with increased systemic IL-10 levels

BACKGROUND: Recurrence of hepatitis C after liver transplantation is an almost universal occurrence. T-cell derived cytokines have an important role in the development of liver damage associated with chronic hepatitis C, their post-transplant levels, however, have not been correlated with histologic recurrence of the disease. AIMS: We sought to analyze levels of TNF-alpha, soluble IL-2 receptor, IL-4 and IL-10 at 1 month, 6 months and 1 year after transplantation in 27 patients undergoing transplantation for hepatitis C related end-stage liver disease. METHODS: HCV RNA levels were monitored by a branched-chain DNA signal amplification assay. Diagnosis of recurrent hepatitis was based on 1-year protocol biopsies and on biopsies performed for liver enzyme elevations. RESULTS: Recurrent hepatitis C was detected in 52% (n=14) of the 27 patients. HCV RNA levels rose over time in all patients regardless of histologic recurrence. TNF-alpha, and IL-4 levels, although elevated, did not show specific patterns over time or in correlation with recurrence. Similarly, the early elevation followed by a gradual decrease over the first year in the amount of soluble IL-2 receptor was not related to histologic recurrence. We observed a significant increase in circulating IL-10 levels over the first year in patients with biopsy-proven recurrence, while patients with no signs of histologic recurrence displayed increased, but steady levels. CONCLUSIONS: These results suggest that while these cytokines are associated with post-transplant recurrence of hepatitis C, their production may be altered by additional factors.