The impact of ileal pouch-anal anastomosis on graft survival following liver transplantation for primary sclerosing cholangitis.

BACKGROUND: Liver transplantation is the only life-extending intervention for primary sclerosing cholangitis (PSC). Given the co-existence with colitis, patients may also require colectomy; a factor potentially conferring improved post-transplant outcomes. AIM: To determine the impact of restorative surgery via ileal pouch-anal anastomosis (IPAA) vs retaining an end ileostomy on liver-related outcomes post-transplantation. METHODS: Graft survival was evaluated across a prospectively accrued transplant database, stratified according to colectomy status and type. RESULTS: Between 1990 and 2016, 240 individuals with PSC/colitis underwent transplantation (cumulative 1870 patient-years until first graft loss or last follow-up date), of whom 75 also required colectomy. A heightened incidence of graft loss was observed for the IPAA group vs those retaining an end ileostomy (2.8 vs 0.4 per 100 patient-years, log-rank P = 0.005), whereas rates between IPAA vs no colectomy groups were not significantly different (2.8 vs 1.7, P = 0.1). In addition, the ileostomy group experienced significantly lower graft loss rates vs. patients retaining an intact colon (P = 0.044). The risks conferred by IPAA persisted when taking into account timing of colectomy as related to liver transplantation via time-dependent Cox regression analysis. Hepatic artery thrombosis and biliary strictures were the principal aetiologies of graft loss overall. Incidence rates for both were not significantly different between IPAA and no colectomy groups (P = 0.092 and P = 0.358); however, end ileostomy appeared protective (P = 0.007 and 0.031, respectively). CONCLUSION: In PSC, liver transplantation, colectomy + IPAA is associated with similar incidence rates of hepatic artery thrombosis, recurrent biliary strictures and re-transplantation compared with no colectomy. Colectomy + end ileostomy confers more favourable graft outcomes.

Pediatric Liver Transplant Recipients Who Undergo Transfer to the Adult Healthcare Service Have Good Long-Term Outcomes.

Liver transplantation has transformed survival for children with liver disease necessitating the transfer of a growing number of patients to the adult healthcare service. The impact of transfer on outcomes remains unclear. The aim of this single-center study of 137 consecutive pediatric liver transplant recipients was to examine the effect of transfer on patient and graft survival. The median time from transplant to transfer was 10.4 years and the median age of the patients at transfer was 18.6 years. After transfer, there were 5 re-transplants and 12 deaths in 14 patients. The estimated posttransfer 10-year patient and graft survival was 89.9% and 86.2%, respectively. Overall, 4 patients demonstrated graft loss as a consequence of chronic rejection. Graft loss was associated with older age at first transplant (p = 0.008). When compared to young adult patients transplanted in the adult center, the transferred patients did not have inferior graft survival from the point of transfer (HR 0.28; 95% CI 0.10-0.77, p = 0.014). This suggests that transfer did not impact significantly on graft longevity. In conclusion, pediatric liver transplant recipients who undergo transfer to the adult service have good long-term outcomes.

Long-term impact of liver transplantation on respiratory function and nutritional status in children and adults with cystic fibrosis.

Early liver transplant (LT) has been advocated for patients with cystic fibrosis liver disease (CFLD) and evidence of deterioration in nutritional state and respiratory function to prevent further decline. However, the impact of single LT on long-term respiratory function and nutritional status has not been adequately addressed. We performed a retrospective analysis of the outcomes of 40 (21 adult/19 pediatric) patients with CFLD transplanted between 1987 and 2009 with median follow-up of 47.8 months (range 4-180). One and five-year actuarial survival rates were 85%/64% for adult and 90%/85% for pediatric LT cohorts, respectively. Lung function remained stable until 4 years (FEV(1) % predicted; pretransplant 48.4% vs. 45.9%, 4 years posttransplant) but declined by 5 years (42.4%). Up to 4 years posttransplant mean annual decline in FEV(1) % was lower (0.74%; p = 0.04) compared with the predicted 3% annual decline in CF patients with comorbidity including diabetes. Number of courses of intravenous antibiotics was reduced following LT, from 3.9/year pretransplant to 1.1/year, 5 years posttransplant. Body mass index was preserved posttransplant; 18.0 kg/m(2) (range 15-24.3) pretransplant versus 19.6 kg/m(2) (range 16.4-22.7) 5 years posttransplant. In conclusion, LT is an effective treatment for selected patients with cirrhosis due to CFLD, stabilizing aspects of long-term lung function and preserving nutritional status.

Post-transplant lymphoproliferative disease in liver transplantation.

Post-transplant lymphoproliferative disease (PTLD) is a well recognized complication of solid organ transplantation and therapeutic immunosuppression, first reported in 1968. PTLD incorporates a spectrum of abnormalities ranging from a benign infectious mononucleosis-like illness to non-Hodgkin's lymphoma with nodal and extranodal site involvement. The first liver transplant was performed at our institution in January 1982. This retrospective study examined the incidence of PTLD, reason for the original transplants, presenting symptoms, radiological findings, immunosuppression regimens and outcomes of these patients. From a total of 2005 adult liver transplants, 23 patients (1.1%) were identified with PTLD. The average age of these patients at the time of transplant was 46.5 years, with a ratio of female-to-male of 14:9. Indication for transplant ranged from primary biliary cirrhosis (eight patients) to epitheloid haemangioendothelioma (one patient). The average time interval between transplant and diagnosis of PTLD was 50 months. Imaging abnormalities identified included generalized lymphadenopathy, liver and portal masses, splenic enlargement, bowel, eye, cerebral and neck involvement; and in two patients, no radiological abnormality. The most common histological findings ranged from B-cell non-Hodgkin's lymphoma (five patients) to early PTLD in one patient. Our rate of PTLD is lower compared with published literature and demonstrates a much longer time interval from transplant to occurrence of PTLD than previously appreciated. This could be secondary to a low immunosuppression therapy followed at our institution. From a few months to several years after liver transplantation, the radiologist needs to be alert to the possibility of PTLD and thorough imaging is required to detect the wide variety of potential presentations.

Liver resection for colorectal metastases.

BACKGROUND: Colorectal cancer is the second commonest malignancy in the UK. Metastases to the liver occur in greater than 50% of patients and remain the biggest determinant of outcome in these patients. Liver resection is a safe procedure that achieves good long-term survival, but surgery has traditionally been limited to select groups of patients. The improved outcome suggests that more patients could benefit from resection if more was known of what criteria are predictive of a good outcome. PATIENTS AND METHODS: A retrospective analysis was performed on all patients undergoing surgical resection of the liver for colorectal metastases between March 1989 and March 2001 in the Birmingham Liver Unit. RESULTS: During this period, 212 liver resections for colorectal cancer metastases were performed in 82 females and 130 males. The median follow-up was 16 months with an overall actuarial survival of 86% at 1 year, 54% at 3 years, and 28% at 5 years. The peri-operative mortality was 2.8%. The number and timing (metachronous or synchronous) of metastatic lesions, the gender of the patient, pathological staging of the primary lesion or surgical resection margins had no significant influence on survival. Patients with lesions less than 5 cm in size had a significantly prolonged survival compared with patients with lesions greater than 5 cm in size (P < 0.004). CONCLUSIONS: Liver resection is the only curative treatment for patients with colorectal metastases. The long-term survival reported in patients with resected colorectal metastases confined to the liver is comparable to primary surgery for solid gastrointestinal tumours. Every attempt must be made to increase the availability of liver resection to patients with hepatic metastases from colorectal cancer.

Delayed hepatic artery thrombosis in adult orthotopic liver transplantation-a 12-year experience.

BACKGROUND: Although the clinical features of early hepatic artery thrombosis (HAT) are well defined, the features of delayed (more than 4 weeks after transplantation) hepatic artery thrombosis are less clearly defined. The aim of our study was to identify risk factors, clinical presentation, and outcome of management of delayed hepatic artery thrombosis (HAT) after liver transplant (LTx). METHODS: An analysis of prospectively collected data of all patients transplanted from 1986 to 1998 was performed. The importance of recipient (age, sex, primary indication for LTx, cytomegalovirus status, and intraabdominal sepsis) and donor factors (donor age, cold ischemia time, and donor cytomegalovirus status), modes of presentation, and outcome of treatment (biliary reconstruction/stenting, regraft, vascular reconstruction, observation) were analyzed. RESULTS: Delayed HAT was seen in 31/1097 adult LTx recipients (incidence 2.8%). No recipient or donor factors were identified as risk factors. A total of 16 patients were symptomatic at presentation (HAT diagnosed on abdominal ultrasound). Six patients had recurrent episodes of cholangitis, four had cholangitis with a stricture, four had cholangitis and intrahepatic abscesses, and two had bile leaks. Biliary reconstruction was done in six patients (all of whom subsequently required a regraft), vascular reconstruction was performed in two patients (one regrafted and one died shortly after), four patients with cholangitis and stricture on presentation had a biliary stent (all four were later regrafted). A total of 16 patients were regrafted, 9 are alive, 5 died within 6 months (septic at time of LTx), 1 died after 1 year, and 1 died after 2 years. Fifteen patients were asymptomatic and detected on routine screening. 5 have remained asymptomatic and are still alive, 1 developed a biliary stricture that was stented and is alive 105 months later, 4 had recurrence of the original disease, 3 developed progressive graft failure and were listed for transplant but died before regraft due to overwhelming sepsis and hepatic encephalopathy. Two patients died due to nonbiliary sepsis. CONCLUSIONS: Delayed HAT is a rare complication of LTx that may present with biliary sepsis, or remain asymptomatic. Biliary or vascular reconstructions do not increase graft survival. Of the patients who were clinically silent on presentation, 20% developed progressive graft failure requiring a second transplant. A total of 33% survived in the long-term without a second transplant. Ongoing severe sepsis at the time of regraft results in poor survival.

Outcome of liver resection and transplantation for fibrolamellar hepatocellular carcinoma.

Fibrolamellar hepatocellular carcinoma (FL HCC) is an uncommon variant of hepatocellular carcinoma occurring usually in non-cirrhotic livers. Hepatic resection or transplantation offers the only chance of cure. We reviewed our experience of surgery for FL HCC from 1985-1998. Twenty patients with FL HCC (13 females and 7 males) median age 27 years (range 12-69) were treated either by hepatic resection [n = 11; extended right hepatectomy (5), extended left hepatectomy (1), right hemihepatectomy (2), left hemihepatectomy (2), left lateral segmentectomy (1)] or, if the disease was non-resectable, by transplantation (n = 9). The median follow up was 25 months (1-63). The prognostic factors analysed included size [less than 5 cm (3 patients), more than 5 cm (17 patients)], number [solitary (16 patients), multiple (4 patients)], capsular invasion (6 patients), vascular invasion (11 patients) and lymph node invasion (6 patients). The overall survival at 1, 3 and 5 years was 89.5, 75 and 50%, respectively. The liver resection survival was better than liver transplantation survival at 3 years 100 vs 76%, respectively (P < 0.025). Although all prognostic factors analysed did not show a significant difference, there is tendency that tumour stage was the most significant for prognosis. Most of the patients in this study are young and presented without specific symptoms, with normal liver function range and had no tumour marker to help in diagnosis. As a result most of our patients were diagnosed late. However the outcome of surgical intervention was favourable.

Circulating soluble vascular adhesion protein 1 accounts for the increased serum monoamine oxidase activity in chronic liver disease.

BACKGROUND & AIMS: Vascular adhesion protein 1 (VAP-1) is an endothelial glycoprotein that supports adhesion of lymphocytes to hepatic endothelium and has sequence homology with semicarbazide-sensitive amine oxidases (SSAOs). We investigated whether soluble VAP-1 (sVAP-1) displays SSAO activity and thereby accounts for increased monoamine oxidase activity in the serum of patients with liver diseases. METHODS: sVAP-1 concentration and SSAO activity were measured in peripheral, hepatic, and portal blood and in bile from patients with liver disease and in peripheral blood of control subjects, using enzyme-linked immunosorbent assay and enzymatic assays. RESULTS: sVAP-1 concentration (mean [+/-SE], 143. 67 [34.97-92.67] ng/mL) and SSAO activity (18.8 [12.0-24.6] nmol. mL(-1). h(-1)) were significantly increased in chronic liver diseases compared with healthy controls (87.1 [53.5-127] ng/mL [P<0.001] and 10.7 [6.5-12.7] nmol. mL(-1) x h(-1) [P<0.05]) but not in massive necrosis caused by paracetamol poisoning (109 [80.3-140] ng/mL and 8.9 [5.7-12.3] nmol. mL(-1) x h(-1)). sVAP-1 correlated with serum transaminase and bilirubin but not with creatinine. In 5 paired samples, sVAP-1 concentration was higher in hepatic (median, 113 [range, 53-122]) than in portal vein (102 [42-109]; 2P<0.05), and was not detected in bile. There was a highly significant correlation between serum sVAP-1 and SSAO activity in normal subjects, patients with acute liver failure, and those with chronic liver disease (r = 0.895; P<0.001). When serum was depleted of sVAP-1 by immunoaffinity chromatography, SSAO activity was eliminated. CONCLUSIONS: sVAP-1 levels are increased in chronic liver disease, and sVAP-1 is likely derived from the liver. Serum sVAP-1 displays SSAO activity and accounts for most of the monoamine oxidase activity in human serum.

Outcome of liver retransplantation in children.

Irreversible liver graft failure is a life-threatening complication. We reviewed the first 200 pediatric liver transplantations in Birmingham. Forty-one children developed primary graft failure, 9 of whom developed secondary graft failure. The main indications for graft failure were primary nonfunction (PRNF; 8 patients), vascular complications (VASC; 23 patients), and chronic rejection (CHRE; 19 patients). Thirty-two children underwent retransplantation (ReTx) (21 children received reduced grafts; 11 children, whole hepatic grafts). Patient survival was significantly worse for retransplant recipients compared with children receiving a single graft (63% v 76. 5% actuarial patient survival at 1 year; P <.05). Primary graft 1-year actuarial survival was 74% in first grafts compared with 47% for regrafts (P <.05), but improved with time. The graft 1-year survival rate was 55% for whole grafts and 45% for reduced and/or split grafts in the first 100 grafts compared with 83% and 66% in the second 100 grafts, respectively (P <.01). Emergency ReTx within a month of transplantation was associated with more complications and a worse outcome (1-year survival rate, 37%) compared with patients who underwent ReTx later (1-year survival rate, 72%; P <. 01). The incidence of primary graft failure decreased from 33% in the first 100 grafts to 16% in the second 100 grafts (P <.01), as did the incidence of PRNF, which decreased from 8% to 0% (P <.05). Although the rates of graft failure from VASC decreased from 15% to 8% (P =.2) and CHRE decreased from 11% to 8% (P =.6), neither reached statistical significance. The improved results overall are because of advances in surgical techniques, intensive care management, and graft preservation and refinements in immunosuppression. We conclude that ReTx for a child with primary graft failure is justified.

Poor outcome in patients with diabetes mellitus undergoing liver transplantation.

BACKGROUND: Relatively few studies have examined the influence of pretransplant diabetes on survival after an orthotopic liver transplant (OLT), and those published to date show only minor increases in infection rates among diabetics and no increase in mortality. METHODS: We examined the effect of diabetes mellitus on survival after OLT. 1005 adults underwent OLT between 1982 and May 1997. Seventy-eight patients with pretransplant diabetes mellitus (7.8% of all OLT, 38 insulin treated, 25 tablet treated, 15 diet controlled) were identified and compared with controls matched for age, sex, and date of first transplant and also with all nondiabetic adult liver recipients undergoing OLT during the same period. RESULTS: In patients undergoing OLT survival was worse in diabetics than in the comparison group (P=0.002) and vs. all adult nondiabetics undergoing (n=927) (P=0.004); in diabetics with alcoholic liver disease (ALD) vs. all nondiabetics with alcoholic liver disease (P= <0.0001); and in insulin-treated compared with non-insulin-treated diabetics (P=0.05). Multivariate analysis showed type of diabetes (P=0.001) and ALD (P=0.024) to be the most significant independent variables adversely affecting survival. Survival in diabetics undergoing OLT could be further stratified according to whether diabetics were insulin treated. CONCLUSIONS: Poorer outcome in the diabetics undergoing OLT, particularly in those with ALD, suggests the need for a more detailed pre-OLT assessment of these patients, particularly those with insulin and tablet controlled diabetes.

Chronic renal failure following liver transplantation: a retrospective analysis.

BACKGROUND: Liver transplant recipients are at risk of chronic renal disease, principally as a result of nephrotoxicity of the commonly used immunosuppressive agents cyclosporine and tacrolimus. We have investigated the incidence of chronic renal failure and its risk factors in our transplant population, which was treated predominantly with cyclosporine. METHODS: A single-center retrospective study was done of 883 consecutive adult patients receiving a first liver transplant between 1982 and 1996. Potential risk factors for the development of chronic renal failure were recorded, including serial measurements of cyclosporine therapy and renal function. RESULTS: Severe chronic renal failure (serum creatinine level >250 microM/L for at least 6 months) developed in 25 patients, representing 4% of patients surviving 1 year or more. Twelve of these patients developed end-stage renal failure and mortality was 44%. The predominant cause of renal failure was cyclosporine nephrotoxicity. Serum creatinine as early as 3 months after surgery was strongly associated with the eventual development of severe chronic renal failure (P=0.001), and this group could be further subdivided into two groups with differing risk factors. The first group had early (<1 year) renal dysfunction, with older age (P=0.03), cytomegalovirus infection (P=0.03), need for perioperative renal replacement therapy (P=0.06), and regrafting (P=0.06) as risk factors for eventual renal failure; the second group had late-onset (>1 year) renal dysfunction, with cyclosporine levels at 1 month after surgery (P=0.007) and daily and cumulative cyclosporine dosage at 5 years (P=0.01 for both) as risk factors. CONCLUSIONS: With improved survival of liver transplant recipients, chronic renal failure has become an important cause of morbidity and is associated with a high mortality. Many patients at risk of severe chronic renal failure may be identified at an early stage. Treatment regimens that avoid or prevent cyclosporine-induced nephrotoxicity are urgently required for this population.

Repeat orthotopic liver transplantation in the 1990s: is it justified?

Repeat orthotopic liver transplantation (ReOLT) is controversial because of limited donor organ availability and increasing health care costs. The purpose of this study is to analyse and compare the outcome of reOLT in the 1990s and the 1980s. Prospective data of 1077 adult OLT from the Liver Unit database were used for the study. The log-rank test was used for statistical analysis. Between January 1982 and December 1996, a total of 1077 adult OLTs were performed including 107 reOLTs. The proportion of retransplants decreased from 13% in the 1980s to 9% in the 1990s. There was a significant improvement in outcome; the overall 1-year graft and patient survival for reOLT was 60% and 74% in the 1990s compared to 29% (P < 0.0001) and 51% (P < 0.0001) in the 1980s. In the second half of the study between January 1990 and December 1996, 732 adult OLTs were undertaken including 70 (9%) reOLTs which consisted of 62 second, 7 third and 1 fourth grafts. The main indications for retransplantation were chronic rejection (31%), hepatic artery thrombosis (30%), primary non-function (16%), ischaemic injury (11%), recurrent disease (6%) and biliary complications (6%). During this period, the 1-year graft survival for all reOLTs was significantly lower than for primary OLTs (67% vs 78%, P < 0.001). The timing of reOLT was found to be associated with graft survival; 1-year graft survival for early reOLT (< 30 days) was 50% compared to 73% for late reOLT (P < 0.001). The worse outcome associated with early reOLT is explained by the poor preoperative medical condition of patients who were retransplanted from intensive care. Subgroup analysis of indications for reOLT revealed 1-year graft survival of 81% for late vascular complications, 75% for early vascular complications, 69% for chronic rejection and 30% for primary non-function. One-year graft survival rates for third and fourth grafts were 42% and 0%, respectively. Graft survival and resource utilisation in patients who received a late regraft for the first time is now comparable to that for primary OLT. The favourable overall results should not preclude this group of patients from consideration for reOLT.

Health-related quality of life following liver transplantation.

The objectives of this study were to report on the health-related quality of life (QoL) experienced by patients following liver transplantation and to investigate the factors associated with its variation. A questionnaire comprising the SF-36 and EuroQol EQ-5D instruments was sent by post to 147 patients who had received a liver transplant, indicated by a chronic liver disease, in the previous 8 years. The scores of the respondents were compared to population norm scores. The variation in both the SF-36 and EQ-5D scores was explored. Many liver transplant patients experienced most satisfactory QoL levels post-transplantation although, in general terms, the levels were poorer than those seen in the general population. The variation in the post-transplant health-related QoL scores was found to be associated with a number of pre-transplant factors: disease severity (proxied by Child Pugh class), disease duration at the time of transplantation and liver transplant history (whether the patient had received a single or multiple transplants). In making clinical decisions about the use of transplantation for chronic liver diseases, consideration should be given to the key factors likely to affect subsequent health-related QoL.

A positive crossmatch in liver transplantation--no effect or inappropriate analysis? A prospective study.

BACKGROUND: Controversy over the relationship of preformed lymphocytotoxic antibodies and liver graft outcome remains. Because graft loss associated with preformed lymphocytotoxic antibodies probably occurs early after transplant, analysis of long-term survival is of questionable value. We therefore prospectively analyzed the effect on short- and long-term graft survival of the presence of lymphocytotoxic alloantibody in 207 primary adult liver allograft recipients. METHODS: Pretransplant serum was tested for donor-specific lymphocytotoxic antibodies and panel-reactive antibodies (PRA) using donor splenic lymphocytes and lymphocytes obtained for routine tissue typing. RESULTS: A positive crossmatch was detected in 24 recipients (11.5%): T-cell positive in 11 recipients and B-cell positive in 13 recipients. PRA were detected in 68 of 179 recipients tested (37.4%). High T-cell PRA (>55%) was detected in 17 recipients, and high B-cell PRA was detected in 20 recipients. Low PRA (<15%) against T cells was detected in 19 recipients and against B cells in 24 recipients. Graft failures occurred in 5 of 24 (21%) crossmatch-positive recipients and in 7 of 172 (4%) crossmatch-negative recipients. Graft survival was significantly lower in crossmatch-positive recipients at 1 month after transplant (chi-square=10.3, P=0.00133) but not at 3 months or 1 year. Causes of early graft loss were associated with immunological mechanisms, whereas later losses were due to nonimmunological mechanisms. CONCLUSIONS: Early graft loss may be increased in those recipients who are crossmatch positive. However, the logistical problems and consequences associated with allocation probably outweigh the benefits of prospective crossmatching.

Progress in pediatric liver transplantation--the Birmingham experience.

This report describes the evolution of the Birmingham, UK experience with pediatric liver transplantation from 1983 to present. Two hundred liver grafts were placed in 168 children less than 17 years of age. The current survival rate exceeds 80%.

Glycogen content of the donor liver and its relation to postreperfusion hepatic energy metabolism.

OBJECTIVES: Many studies have suggested that glycogen in donor livers is an important fuel during cold ischemic time and at reperfusion. However, it remains unclear as to whether the depression of glycogen content in the graft results in a critical derangement of energy metabolism after reperfusion. The purpose of this study was to assess the possible implications of the glycogen concentration of donor livers for the hepatic energy metabolism after reperfusion. METHODS: The glycogen content of 28 donor livers and the plasma concentrations of metabolic substrates were measured during liver transplantation. RESULTS: Gluconeogenesis was maintained even in the glycogen-depleted graft at reperfusion. However, glycogen-depleted grafts produced more ketone bodies until 24 h after reperfusion. Free carnitine concentrations in these patients were significantly higher than those in the patients with glycogen-nondepleated grafts until 48 h after reperfusion. CONCLUSIONS: A glycogen-depleted liver graft may restore essential metabolic function by producing energy substrates through enhanced ketogenesis in the postreperfusion period. The enhanced production of carnitine by the graft provides a substrate for the production of ketone bodies and thus may be relevant to the enhanced ketogenesis.