Glenn A. Halff

Liver transplantation for the Budd-Chiari syndrome

Orthotopic liver transplantation was accomplished in a 22-year-old woman dying of the Budd-Chiari syndrome. She is well and has normal liver function 16 months postoperatively. In view of the good early result, it will be appropriate to consider liver replacement for this disease in further well-selected cases.

Pancreatic islet amyloidosis, β-cell apoptosis, and α-cell proliferation are determinants of islet remodeling in type-2 diabetic baboons

β-Cell dysfunction is an important factor in the development of hyperglycemia of type-2 diabetes mellitus, and pancreatic islet amyloidosis (IA) has been postulated to be one of the main contributors to impaired insulin secretion. The aim of this study was to evaluate the correlation of IA with metabolic parameters and its effect on islets of Langerhans remodeling and relative endocrine-cell volume in baboons. We sequenced the amylin peptide, determined the fibrillogenic propensities, and evaluated pancreatic histology, clinical and biochemical characteristics, and endocrine cell proliferation and apoptosis in 150 baboons with different metabolic status. Amylin sequence in the baboon was 92% similar to humans and showed superimposable fibrillogenic propensities. IA severity correlated with fasting plasma glucose (FPG) (r = 0.662, P < 0.001) and HbA1c (r = 0.726, P < 0.001), as well as with free fatty acid, glucagon values, decreased homeostasis model assessment (HOMA) insulin resistance, and HOMA-B. IA severity was associated with a decreased relative β-cell volume, and increased relative α-cell volume and hyperglucagonemia. These results strongly support the concept that IA and β-cell apoptosis in concert with α-cell proliferation and hypertrophy are key determinants of islets of Langerhans “dysfunctional remodeling” and hyperglycemia in the baboon, a nonhuman primate model of type-2 diabetes mellitus. The most important determinants of IA were age and FPG (R2 = 0.519, P < 0.0001), and different FPG levels were sensitive and specific to predict IA severity. Finally, a predictive model for islet amyloid severity was generated with age and FPG as required variables.

Impact of Recipient MELD Score on Resource Utilization

The model for end stage liver disease (MELD) system prioritizes deceased donor organs to the sickest patients who historically require higher healthcare expenditures. Limited information exists regarding the association of recipient MELD score with resource use. Adult recipients of a primary liver allograft (n = 222) performed at a single center in the first 27 months of the MELD system were analyzed. Costs were obtained for each recipient for the 12 defined categories of resource utilization from the time of transplant until discharge. True (calculated) MELD scores were used. Inpatient transplant costs were significantly associated with recipient MELD score (r= 0.20; p = 0.002). Overall 1‐year patient survival was 85.0% and was not associated with MELD score (p = 0.57, log rank test). Recipient MELD score was significantly associated with costs for pharmacy, laboratories, radiology, dialysis and physical therapy. Multivariate linear regression revealed that MELD score was most strongly associated with cost compared to other demographic and clinical factors. Recipient MELD score is correlated with transplant costs without significantly impacting survival.

Steroid elimination 24 hours after liver transplantation using daclizumab, tacrolimus, and wcophenolate mofetil

BACKGROUND Corticosteroids have long been a cornerstone of orthotopic liver transplant (OLTx) immunosuppression. Newer, more potent, agents have successfully allowed for more rapid tapering and discontinuation of corticosteroids in OLTx recipients. We hypothesize that corticosteroids can be safely avoided after the first postoperative day (POD) using these newer agents. METHODS Thirty adult OLTx recipients were prospectively enrolled in a randomized open-label, institutional review board-approved protocol. Fifteen patients (group A) received our standard regimen of tacrolimus, mycophenolate mofetil, and corticosteroids, and 15 patients (group B) received daclizumab, 2 mg/kg on POD 0 and 14, with tacrolimus, mycophenolate mofetil, and corticosteroids on POD 0 and 1 and then discontinuation. In both groups, mycophenolate mofetil was tapered off between 3 and 4 months after OLTx. Bone mineral densitometry was performed at 1, 3, and 6 months after OLTx. Quantitative hepatitis C virus (HCV) polymerase chain reaction was obtained at days 0, 7, 14, 21, and 28. Retransplant recipients, patients with autoimmune hepatitis, or status 1 or 2A patients were excluded. RESULTS Patient and graft survival rates were 93% (group A) and 100% (group B) with mean follow-up of 18 months. Patients in group B had more rejection diagnosed (25%) compared with group A (6.7%). Yet, the incidence of biopsy-proven acute rejection requiring steroid therapy was 6.7% in both groups. Hispanic race was common in groups A and B (87% and 74%). A total of six biopsies were performed in group B, with three patients having mild rejection responding to an increase in tacrolimus without the need for corticosteroids. One patient in group B was switched to cyclosporine for severe neurotoxicity and remains on monotherapy with normal graft function. No patient in either group developed a requirement for additional antihypertensive medication. Likewise, there were no patients with new-onset diabetes. The bone mineral densitometry was higher in group B at every time point but did not reach statistical significance. Serum cholesterol level was significantly (P=0.03) lower in group B at 6 months after OLTx. Serum triglycerides were also lower, but the difference was not significant. Quantitative polymerase chain reaction for HCV-positive patients (group A, n=7; group B, n=8) frequently increased after OLTx. There was no correlative decrease associated with daclizumab. At present, two patients in group A have documented HCV recurrence. CONCLUSION Corticosteroids can be safely avoided after POD 1 with the current regimen. With early follow-up, there is no difference in hypertension or diabetes or bone density. Lipid panels tended to be lower in patients who were not on corticosteroids. Longer term follow-up will be needed to demonstrate the potential advantage of corticosteroid avoidance in regard to hypertension, diabetes, and possibly HCV recurrence.

Investigation and control of aspergillosis and other filamentous fungal infections in solid organ transplant recipients.

Filamentous fungal infections are associated with high morbidity and mortality in solid organ transplant patients, and prevention is warranted whenever possible. An increase in invasive aspergillosis was detected among solid organ transplant recipients in our institution during 1991–92. Rates of Aspergillus infection (18.2%) and infection or colonization (42%) were particularly high among lung transplant recipients. Epidemiologic investigation revealed cases to be both nosocomial and community‐acquired, and preventative efforts were directed at both sources. Environmental controls were implemented in the hospital, and itraconazole prophylaxis was given in the early period after lung transplantation. The rate of Aspergillus infection in solid organ transplant recipients decreased from 9.4% to 1.5%, and mortality associated with this disease decreased from 8.2% to 1.8%. The rate of Aspergillus infection or colonization among lung transplant recipients decreased from 42% to 22.5%; nosocomial Aspergillus infection decreased from 9% to 3.2%. Cases of aspergillosis in lung transplant recipients were more likely to be early infections in the pre‐intervention period. Early mortality in lung transplant recipients decreased from 15% to 3.2%. Two cases of dematiaceous fungal infection were detected, and no further cases occurred after environmental controls. The use of environmental measures that resulted in a decrease in airborne fungal spores, as well as antifungal prophylaxis, was associated with a decrease in aspergillosis and associated mortality in these patients. Ongoing surveillance and continuing intervention is needed for prevention of infection in high‐risk solid organ transplant patients.

Radiofrequency tissue ablation: Effect of hepatic blood flow occlusion on thermal injuries produced in cirrhotic livers

AbstractBackground: Radiofrequency thermal ablation has been used as a treatment for several types of hepatic malignancies. Many of these lesions exist in the presence of cirrhosis. Limitations exist to the size of the ablations and, subsequently, the efficacy of treatment. Hepatic vascular inflow occlusion has been advocated as an adjunctive measure to increase the efficacy of the ablation. We present a model in the human cirrhotic liver that demonstrates the advantage of blood flow occlusion during radiofrequency ablation. Methods: Five patients with advanced endstage liver disease scheduled to have orthotopic liver transplantation were enrolled in this study. After laparotomy and before hepatectomy, radiofrequency ablation was performed without and with hepatic blood flow occlusion. After hepatectomy, the liver was sectioned, the area of ablation was measured in three dimensions, and the volume of ablation calculated. Results: Three of the patients had had previously placed transjugular intrahepatic portosystemic shunt. The mean volume of the ablation without blood flow occlusion was 22.5 ± 7.4 cm3 and that with blood flow occlusion was 48.4 ± 24.0 cm3 (P = .05). Conclusions: Ablation area is increased significantly with hepatic blood flow occlusion in the human cirrhotic liver. This result may have application in the treatment of larger (>3 cm) hepatic malignancies.

Factors influencing liver transplant length of stay at two large‐volume transplant centers

Length of stay (LOS) is considered a reliable surrogate for liver transplant resource utilization. Little information exists about how donor and recipient variables interact to affect transplant LOS. Data for adult, non–status 1 transplants (1998–2005), including the donor risk index (DRI) and Model for End‐Stage Liver Disease (MELD) scores, were collected from 2 institutions (n = 745 for center A and n = 710 for center B). Cox proportional hazards models identified variables associated with LOS for the separate and combined cohorts. The cohorts differed significantly in donor, recipient, and transplant factors. DRI (1.46 for center A and 1.40 for center B, P = 0.0013) and MELD (22.4 for center A and 20.4 for center B, P = 0.046) were both higher at center A, but LOS was comparable (13.7 days for center A and 13.3 days for center B, P = 0.052). Three factors at center A (nonlocal donor, recipient age, and MELD) and 7 factors at center B (donor age and weight, recipient female gender, retransplant status, international normalized ratio, MELD, and cold ischemia time) were associated with transplant LOS. For the combined cohort, donor age, weight, nonlocal status, recipient age, female gender, retransplant status, MELD, and transplant center were LOS risk factors. In conclusion, the impact of donor and recipient variables on LOS varies by institution. However, the MELD score exerts a potent and consistent effect across institutions, emphasizing the dominant role of disease severity in liver transplant resource utilization. Liver Transpl 15:1570–1578, 2009.

Split-liver transplantation: results of statewide usage of the right trisegmental graft.

Split‐liver transplantation (SLT) effectively expands the cadaveric donor pool for children. The remaining right trisegmental (RTS) graft can be transplanted into adults. Limited information exists regarding the outcomes of RTS allografts. Sixty‐five RTS graft recipients from five adult transplant programs in Texas were identified. Donor and recipient information were analyzed retrospectively. Most livers (75%) were originally allocated to pediatric recipients. Liver splitting occurred via the in situ (72%) and ex situ (28%) techniques. Arterial reconstruction of RTS grafts was common (52%). Patient and graft survival at 3 months were comparable for the in situ and ex situ techniques (p = 0.2). Cox regression showed only in situ splitting to be a predictor of outcome longer than 3 months posttransplant. Sharing of grafts between centers was frequent (37% of total). One‐year patient and allograft survival (87.1% and 85.4%) were excellent with no cases of primary nonfunction. SLT consistently generates two functional liver allografts with excellent recipient survival. In situ splitting of the liver is the preferred technique. Decreased survival is observed with RTS graft use in higher risk recipients. Broader application of SLT with increased sharing is feasible and safely expands the number of liver allografts that can be transplanted.

An Early Regional Experience with Expansion of Milan Criteria for Liver Transplant Recipients

The Milan Criteria (MC) showed that orthotopic liver transplantation (OLT) was an effective treatment for patients with nonresectable, nonmetastatic HCC. There is growing evidence that expanding the MC does not adversely affect patient or allograft survival following OLT.

Acute hepatic allograft rejection: a comparison of patients with and without centrilobular alterations during first rejection episode.

The histologic diagnosis of acute hepatic allograft rejection is usually based upon the identification of characteristic portal tract features. In addition to these, centrilobular alterations such as central vein endothelialitis, zone 3 inflammation, and hepatocyte necrosis may also be seen during episodes of acute rejection. The purpose of this study was to identify any differences in the subsequent clinical course of patients with and without centrilobular alterations during their first biopsy‐proven episode of acute rejection. Acute rejection was diagnosed at least once in 35 liver recipients who had undergone allograft biopsy. Of these, 15 (43%) had centrilobular alterations in their first posttransplant biopsy. These 15 patients developed ductopenia (60% vs. 30%) and subsequent episodes of acute rejection (53% vs. 25%) more often than did the 20 patients who lacked centrilobular alterations in their first posttransplant biopsy. Time to first episode of acute rejection and rates of subsequent recurrent hepatitis and death were similar between the 2 groups. Patients with centrilobular alterations during a first episode of acute rejection are more likely to have subsequent episodes of acute rejection and to develop features of chronic rejection than are patients without these changes. These patients may benefit from more vigilant clinical follow‐up and/or higher levels of immunosuppression. (Liver Transpl 2004;10:369–373.)