Liver Transplantation for Severe Alcoholic Hepatitis: Report of a Single Center Pilot Program.

BACKGROUND: Liver transplantation (LT) can significantly improve mortality for severe alcoholic hepatitis (AH). However, this practice remains controversial. Our aim is to report the findings from our institution regarding outcomes for LT in severe AH and to discuss the results of a pilot program for discharging selected patients with close follow-up, in order to demonstrate sustained outpatient sobriety before listing. METHODS: Patient records were reviewed retrospectively from January 1, 2015 to January 17, 2018. The primary outcomes were patient and graft survival after LT. Secondary outcomes included relapse rates after LT, survival for those not transplanted, and reasons for denial among those not approved for transplant listing. RESULTS: A total of 18 patients with severe AH were considered for LT, of which 10 were transplanted and 8 were either denied transplantation or died before completing the evaluation. Patient and graft survival rates were 100% among those transplanted, and only 1 of the 10 patients (10%) returned to harmful drinking. In comparison, 6 of 8 (75%) of patients not transplanted died. Among the 10 patients transplanted, 4 were initially not approved for listing and were discharged with close follow-up, to demonstrate outpatient sobriety. All 4 of those patients demonstrated short-term abstinence and ultimately underwent transplantation, with no instances of relapse post-LT. CONCLUSIONS: Liver transplantation for AH can achieve excellent outcomes with low rates of relapse. Carefully selected patients can be discharged with close monitoring to demonstrate commitment to outpatient sobriety prior to transplant listing.

Venovenous Extracorporeal Membrane Oxygenation for Acute Respiratory Failure in a Liver Transplant Patient: A Case Report.

Intraoperative extracorporeal membrane oxygenation (ECMO) support, both venoarterial and venovenous (VV), have been used sparingly and with limited success in the setting of liver transplantation. Here, we report the successful use of VV-ECMO in the resuscitation and pulmonary bridging support after severe systemic inflammatory response in a combined liver and kidney transplant recipient who suffered primary nonfunction of both allografts. Where conventional ventilator maneuvers may prove ineffective, the implementation of VV-ECMO should be considered as a therapeutic option in limited, short-lived acute pulmonary injury.

Outcomes of Highly Sensitized Patients Undergoing Simultaneous Liver and Kidney Transplantation: A Single-Center Experience With Desensitization.

BACKGROUND: Preformed donor-specific human leukocyte antigen antibodies (DSAs) in patients undergoing simultaneous liver and kidney transplantation (SLKT) are an independent risk factor for poorer patient and renal allograft survival. The outcomes of patients highly sensitized (HS) against HLA antigens undergoing SLKT and select HS SLKT recipients undergoing desensitization at a high-volume desensitization center were investigated. METHODS: Seventy-five patients undergoing SLKT at a high-volume desensitization center between January 1, 2001, and December 31, 2015, were retrospectively reviewed. HS patients were defined by panel-reactive antibody (PRA) >30% (n = 17 patients), 11 of whom received pre- or perioperative desensitization with high-dose intravenous immunoglobulin (IVIG) ± rituximab. RESULTS: HS patients had significantly higher class I and class II PRA (class I = 41.3% ± 40.0% vs 2.5% ± 6.3%; class II = 45.7% ± 36.4% vs 1.0% ± 2.9%; P < .001), were more likely to be female (P = .05), and more likely to have had a prior transplant (P = .03). HS patients demonstrated greater susceptibility to renal cell-mediated rejection (CMR) (23.5% vs 5.2%, P = .02) compared to nonsensitized patients. Higher renal antibody-mediated rejection (ABMR) was also observed in HS patients, 11.8% vs 3.4%, but did not reach significance (P = .18). Desensitization in select HS SLKT patients was well tolerated but did not improve patient and allograft survival or significantly curtail rejection. CONCLUSION: HS SLKT recipients demonstrated increased allograft rejection, particularly CMR, but patient and graft survival were not impacted in the first year post-transplant. Select HS SLKT patients tolerated desensitization with high-dose IVIG ± rituximab and may have received additional immunoprotection against ABMR but survival was not affected.

Liver Transplantation in a Patient With CD40 Ligand Deficiency and Hyper-IgM Syndrome: Clinical and Immunological Assessments.

Monoclonal antibodies that disrupt CD40-CD40 ligand (CD40L) interactions are likely to have use in human transplantation. However, the extent of the immunosuppressive effects of CD40-CD40L blockade in humans is unknown. Hyper-IgM syndrome (HIGM) is a rare primary immunodeficiency syndrome characterized by defects in the CD40-CD40L pathway, severe immune deficiency (IgG), and high or normal IgM levels. However, the effects of CD40L deficiency on T- and natural killer (NK)-cell function is not established. Here, we present a patient with HIGM syndrome who underwent liver transplantation for hepatitis C virus infection. Posttransplantation, NK-cell antibody-dependent cytokine release (γ-interferon) to alloantigens and T cell responses to viral antigens and mitogens were assessed and showed normal CD4+ , CD8+ , and NK-cell responses. We also examined antibody-dependent cellular cytotoxicity against a CD40+ and HLA-expressing cell line. These experiments confirmed that the patient's NK cells were equivalent to those of normal subjects in mediating antibody-dependent cellular cytotoxicity despite the absence of CD40-CD40L interactions. Mitogenic stimulation of the patient's peripheral blood mononuclear cells showed no expression of CD40L on T and NK cells compared with increased expression in normal subjects. Taken together, these data suggest that absence of CD40L expression is responsible for aberrant B cell immunity but had little impact on NK- and T cell immune responses in vitro.

Successful Treatment of Mitochondrial Toxicity in an HIV-Positive Patient After Liver Transplantation.

Liver transplantation in patients infected with the human immunodeficiency virus (HIV) has been increasingly performed with reasonable outcomes; however, medical management of both immunosuppression and antiretroviral therapy can be challenging owing to drug toxicities and interactions. Nucleoside reverse transcriptase inhibitors (NRTIs), a common backbone of highly active antiretroviral therapy (HAART), were the first class of effective antiretroviral drugs developed. NRTIs are commonly used for posttransplant HAART therapy and have a rare but fatal complication of mitochondrial toxicity, manifesting as severe lactic acidosis, hepatic steatosis, and lipoatrophy. Herein, we have reported on the first known successful treatment of severe mitochondrial toxicity secondary to NRTIs in an HIV-infected transplant recipient.

Obesity is independently associated with infection in hospitalised patients with end-stage liver disease.

BACKGROUND: Infection is the most common cause of mortality in end-stage liver disease (ESLD). The impact of obesity on infection risk in ESLD is not established. AIM: To characterise the impact of obesity on infection risk in ESLD. METHODS: We evaluated the association between infection and obesity in patients with ESLD. Patients grouped as non-obese, obesity class I-II and obesity class III were studied using the Nationwide Inpatient Sample. Validated diagnostic code based algorithms were utilised to determine weight category and infections, including bacteraemia, skin/soft tissue infection, urinary tract infection (UTI), pneumonia/respiratory infection, Clostridium difficile infection (CDI) and spontaneous bacterial peritonitis (SBP). Risk factors for infection and mortality were assessed using multivariable logistic regression analysis. RESULTS: Of 115 465 patients identified, 100 957 (87.5%) were non-obese and 14 508 (12.5%) were obese, with 9489 (8.2%) as obesity class I-II and 5019 (4.3%) as obesity class III. 37 117 patients (32.1%) had an infection diagnosis. Infection was most prevalent among obesity class III (44.0%), followed by obesity class I-II (38.9%) and then non-obese (31.9%). In multivariable modelling, class III obesity (OR = 1.41; 95% CI 1.32-1.51; P < 0.001), and class I-II obesity (OR = 1.08; 95% CI 1.01-1.15; P = 0.026) were associated with infection. Compared to non-obese patients, obese individuals had greater prevalence of bacteraemia, UTI, and skin/soft tissue infection as compared to non-obese patients. CONCLUSIONS: Obesity is newly identified to be independently associated with infection in end-stage liver disease. The distribution of infection sites varies based on weight category.

Virologic and clinical outcomes of hepatitis B virus infection in HIV-HBV coinfected transplant recipients.

Liver transplantation (LT) is the treatment of choice for end-stage liver disease, but is controversial in patients with human immunodeficiency virus (HIV) infection. Using a prospective cohort of HIV-hepatitis B virus (HBV) coinfected patients transplanted between 2001-2007; outcomes including survival and HBV clinical recurrence were determined. Twenty-two coinfected patients underwent LT; 45% had detectable HBV DNA pre-LT and 72% were receiving anti-HBV drugs with efficacy against lamivudine-resistant HBV. Post-LT, all patients received hepatitis B immune globulin (HBIG) plus nucleos(t)ide analogues and remained HBsAg negative without clinical evidence of HBV recurrence, with a median follow-up 3.5 years. Low-level HBV viremia (median 108 IU/mL, range 9-789) was intermittently detected in 7/13 but not associated with HBsAg detection or ALT elevation. Compared with 20 HBV monoinfected patients on similar HBV prophylaxis and median follow-up of 4.0 years, patient and graft survival were similar: 100% versus 85% in HBV mono- versus coinfected patients (p = 0.08, log rank test). LT is effective for HIV-HBV coinfected patients with complications of cirrhosis, including those who are HBV DNA positive at the time of LT. Combination HBIG and antivirals is effective as prophylaxis with no clinical evidence of HBV recurrence but low-level HBV DNA is detectable in approximately 50% of recipients.

Abdominal compartment syndrome secondary to retroperitoneal hematoma as a complication of ERCP after liver transplantation.

Endoscopic retrograde cholangiopancreatography (ERCP) is frequently employed in the management of postoperative biliary complications in the liver transplant patient. Bleeding after ERCP most commonly presents as gastrointestinal bleeding and often can be managed with repeat endoscopy. ERCP can also be complicated by retroperitoneal hematoma, which in rare cases can lead to hemodynamic compromise due to relentless hemorrhage or from secondary abdominal compartment syndrome. We describe the first reported case of post-ERCP retroperitoneal hematoma in a liver transplant recipient that led to abdominal compartment syndrome and shock liver. We will present the case, discuss management, and review the complications of ERCP in the liver transplant recipient. Close post-procedure monitoring, rapid detection, and low threshold for decompressive laparotomy are keys to the successful management of the liver transplant recipient experiencing expanding retroperitoneal hematoma after ERCP.

Heparin and heparan sulphate protect basic fibroblast growth factor from non-enzymic glycosylation.

Non-enzymic glycosylation of basic fibroblast growth factor (bFGF, FGF-2) has recently been demonstrated to decrease the mitogenic activity of intracellular bFGF. Loss of this bioactivity has been implicated in impaired wound healing and microangiopathies of diabetes mellitus. In addition to intracellular localization, bFGF is also widely distributed in the extracellular matrix, primarily bound to heparan sulphate proteoglycans (HSPGs). Nonetheless, it is not clear if non-enzymic glycosylation similarly inactivates matrix-bound bFGF. To investigate this, we measured the effect of non-enzymic glycosylation on bFGF bound to heparin, heparan sulphate and related compounds. Incubation of bFGF with the glycosylating agents glyceraldehyde 3-phosphate (G3P; 25 mM) or fructose (250 mM) resulted in loss of 90% and 40% of the mitogenic activity of bFGF respectively. Treatment with G3P and fructose also decreased the binding of bFGF to a heparin column. If heparin was added to bFGF prior to non-enzymic glycosylation, the mitogenic activity and heparin affinity of bFGF were nearly completely preserved. A similar protective effect was demonstrated by heparan sulphate, low-molecular-mass heparin and the polysaccharide dextran sulphate, but not by chondroitin sulphate. Whereas non-enzymic glycosylation of bFGF with G3P impaired its ability to stimulate c-myc mRNA expression in fibroblasts, no such impairment was noticeable when bFGF was glycosylated in the presence of heparin. Taken together, these results suggest that HSPG-bound bFGF is resistant to non-enzymic glycosylation-induced loss of activity. Therefore, alteration of this pool probably does not contribute to impaired wound healing seen in diabetes mellitus.

Vascular endothelial growth factor mediates angiogenic activity during the proliferative phase of wound healing.

Angiogenesis is an essential component of normal wound repair, yet the primary mediators of wound angiogenesis have not been well described. The current study characterizes the contribution of vascular endothelial cell growth factor (VEGF) to the angiogenic environment of human surgical wounds. Surgical wound fluid samples (n = 70) were collected daily for up to 7 postoperative days (POD) from 14 patients undergoing mastectomy or neck dissection. VEGF levels in surgical wound fluid were lowest on POD 0, approximating values of serum, but increased steadily through POD 7. An opposite pattern was noted for basic fibroblast growth factor-2. Fibroblast growth factor-2, which has been previously described as a wound angiogenic factor, exhibited highest levels at POD 0, declining to near serum levels by POD 3. Surgical wound fluid form all time points stimulated marked endothelial cell chemotaxis and induced a brisk neovascular response in the rat corneal micropocket angiogenesis assay. Antibody neutralization of VEGF did not affect the in vitro chemotactic or the in vivo angiogenic activity early wound samples (POD 0). In contrast, VEGF neutralization significantly attenuated both chemotactic activity (mean decrease 76 +/- 13%, P < 0.01) and angiogenic activity (5 of 5 samples affected) of later wound samples (POD 3 and 6). The results suggest a model of wound angiogenesis in which an initial angiogenic stimulus is supplied by fibroblast growth factor-2, followed by a subsequent and more prolonged angiogenic stimulus mediated by VEGF.

Thrombospondin 1 synthesis and function in wound repair.

Thrombospondin 1 (TSP1) is a multifunctional extracellular matrix molecule that belongs to a family of homologous glycoproteins. TSP1 can be produced by many cell types that are involved in wound repair, including keratinocytes, fibroblasts, endothelial cells, and macrophages. To investigate the kinetics of TSP1 synthesis in wounds, mRNA from murine full thickness excisional dermal wounds was analyzed. TSP1 mRNA was undetectable in normal skin but was present in early wounds. After day 1, TSP1 mRNA levels within wounds slowly decreased, returning to undectable day 10. In situ hybridization revealed that the primary source of the TSP1 mRNA within wounds was macrophage-like cells in the inflammatory infiltrate. To explore the function of TSP1 production in sites of injury, wounds were treated with antisense TSP1 oligomers. Antisense-treated wounds contained 55 to 66% less TSP1-positive macrophages than control and exhibited a marked delay in repair. This delay included a decreased rate of re-epithelialization as well as a delay in dermal reorganization. The results suggest that TSP1 production by macrophages facilitates the repair process and provide evidence that TSP1 production is an important component of optimal wound healing.

Basic fibroblast growth factor mediates angiogenic activity in early surgical wounds.

BACKGROUND: Wound angiogenesis is believed to be initiated by the early rapid release of performed growth factors such as basic fibroblast growth factor (bFGF). However, neither the angiogenic environment of early surgical wounds nor the potential contribution of bFGF to early surgical wound angiogenesis has been investigated. METHODS: We collected surgical drain fluid (SDF) from closed suction drains 6 hours to 6 days after operation. SDF was tested for endothelial cell (EC) proliferative and chemotactic activity and for the capacity to stimulate angiogenesis in vivo in the rat corneal assay. bFGF levels of SDF were determined with enzyme-linked immunosorbent assay. Neutralizing antibody to bFGF was used to determine the contribution of bFGF to SDF activity. RESULTS: The EC proliferative activity of SDF was maximal on postoperative day 0 (POD 0, 390% that of normal serum) and then fell by 41% on POD 1 and to near serum levels thereafter. SDF from PODs 0 and 1 also showed marked EC chemotactic activity and stimulated rapid formation of new vessels without signs of inflammation when implanted into rat corneas. The temporal appearance of bFGF in these exudates showed a pattern similar to EC proliferative activity, peaking on POD at 854 pg/ml and decreasing 80% by POD 2. Neutralizing antibody to bFGF decreased he proliferative activity of SDF from PODs 0 and 1 to near serum levels and substantially decreased the chemotactic and the in vivo neovascular response to SDFs. CONCLUSIONS: Surgical wounds are characterized by a rapid and early angiogenic environment that is mediated in part by bFGF, suggesting that tissue or platelet stores of bFGF may initiate wound repair.

The solvents cremophor EL and Tween 80 modulate daunorubicin resistance in the multidrug resistant Ehrlich ascites tumor.

Cremophor EL (polyoxyethylene castor oil) and Tween 80, used as solvents for cyclosporin A and VP-16, respectively, were found to reverse the multidrug resistant (MDR) phenotype. In daunorubicin (DNR) resistant Ehrlich ascites tumor cells (EHR2/DNR+), both solvents at percentages of 0.01% (v/v) enhanced DNR accumulation to sensitive levels. Cremophor EL and Tween 80 did not influence DNR accumulation in drug-sensitive cells (EHR2). The concentration of cyclosporin A alone that enhanced DNR accumulation in EHR2/DNR+ cells to sensitive levels was 5 micrograms/mL whereas 0.2 micrograms/mL of cyclosporin A dissolved in 0.001% (v/v) Cremophor EL enhanced DNR accumulation to sensitive levels, thus indicating synergy between Cremophor EL and cyclosporin A. Cyclosporin A had a negligible effect on DNR accumulation in the drug-sensitive cells. In clonogenic assays, the LD10 of DNR was 1 microM in EHR2/DNR+ cells. Combining 1 microM DNR with non-toxic amounts of Cremophor EL (0.001% and 0.002%, v/v) potentiated the cytotoxicity of DNR and resulted in a cell kill of 77% and 86%, respectively, in the resistant cells. In non-toxic amounts, CrEL and Tween 80 acted synergistically with reduced concentrations of verapamil, resulting in DNR accumulation approaching close to the sensitive level. Azidopine photoaffinity labeling of P-glycoprotein in plasma membrane vesicles from EHR2/DNR+ cells was inhibited 100% and 80%, by 0.003% (v/v) Cremophor EL or Tween 80, respectively. These data permit the conclusion that non-toxic amounts of CrEL and Tween 80 modulated DNR resistance by raising intracellular DNR levels, due to their abilities to bind to the plasma membrane P-glycoprotein.