De novo sirolimus and reduced-dose tacrolimus versus standard-dose tacrolimus after liver transplantation: the 2000-2003 phase II prospective randomized trial.

We studied whether the use of sirolimus with reduced-dose tacrolimus, as compared to standard-dose tacrolimus, after liver transplantation is safe, tolerated and efficacious. In an international multicenter, open-label, active-controlled randomized trial (2000-2003), adult primary liver transplant recipients (n=222) were randomly assigned immediately after transplantation to conventional-dose tacrolimus (trough: 7-15 ng/mL) or sirolimus (loading dose: 15 mg, initial dose: 5 mg titrated to a trough of 4-11 ng/mL) and reduced-dose tacrolimus (trough: 3-7 ng/mL). The study was terminated after 21 months due to imbalance in adverse events. The 24-month cumulative incidence of graft loss (26.4% vs. 12.5%, p=0.009) and patient death (20% vs. 8%, p=0.010) was higher in subjects receiving sirolimus. A numerically higher rate of hepatic artery thrombosis/portal vein thrombosis was observed in the sirolimus arm (8% vs. 3%, p=0.065). The incidence of sepsis was higher in the sirolimus arm (20.4% vs. 7.2%, p=0.006). Rates of acute cellular rejection were similar between the two groups. Early use of sirolimus using a loading dose followed by maintenance doses and reduced-dose tacrolimus in de novo liver transplant recipients is associated with higher rates of graft loss, death and sepsis when compared to the use of conventional-dose tacrolimus alone.

Combined liver transplantation and gastric sleeve resection for patients with medically complicated obesity and end-stage liver disease.

Obesity is increasingly common before and after liver transplantation (LT), yet optimal management remains unclear. Our aim was to analyze the effectiveness of a multidisciplinary protocol for obese patients requiring LT, including a noninvasive pretransplant weight loss program, and a combined LT plus sleeve gastrectomy (SG) for obese patients who failed to lose weight prior to LT. Since 2006, all patients referred LT with a BMI > 35 were enrolled. There were 37 patients who achieved weight loss and underwent LT alone, and 7 who underwent LT combined with SG. In those who received LT alone, weight gain to BMI > 35 was seen in 21/34, post-LT diabetes (DM) in 12/34, steatosis in 7/34, with 3 deaths plus 3 grafts losses. In patients undergoing the combined procedure, there were no deaths or graft losses. One patient developed a leak from the gastric staple line, and one had excess weight loss. No patients developed post-LT DM or steatosis, and all had substantial weight loss (mean BMI = 29). Noninvasive pretransplant weight loss was achieved by a majority, though weight gain post-LT was common. Combined LT plus SG resulted in effective weight loss and was associated with fewer post-LT metabolic complications. Long-term follow-up is needed.

Recurrent primary biliary cirrhosis after liver transplantation.

Recurrent primary biliary cirrhosis (PBC) is an important clinical outcome after liver transplantation (LT) in selected patients. Prevalence rates for recurrent PBC (rPBC) reported by individual LT programs range between 9% and 35%. The diagnostic hallmark of rPBC is histologic identification of granulomatous changes. Clinical and biochemical features are frequently absent with rPBC and cannot be used alone for diagnostic purposes. Some of the risk factors of rPBC may include recipient factors such as age, gender, HLA status and immunosuppression, as well as donor factors such as age, gender and ischemic time, although controversy exists. Most patients have early stage disease at the time of diagnosis, and there may be a role for therapy with ursodeoxycholic acid. While short- and medium-term outcomes remain favorable, especially if compared to patients transplanted for other indications, continued follow-up may identify reduced long-term graft and patient survival.

Insulin resistance, serum adipokines and risk of fibrosis progression in patients transplanted for hepatitis C.

In the nontransplant setting diabetes mellitus is a risk factor for disease progression in patients with chronic hepatitis C virus (HCV) infection. The impact of early insulin resistance on the development of advanced fibrosis, even in the absence of clinically apparent diabetes mellitus, is not known. Our aim was to determine whether the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) can be used to identify insulin-resistant patients at risk for rapid fibrosis progression. Cohort study including patients transplanted for chronic HCV between January 1, 1995 and January 1, 2005. One hundred sixty patients were included; 25 patients (16%) were treated for diabetes mellitus and 36 patients (23%) were prediabetic, defined as HOMA-IR >2.5. Multivariate Cox regression analysis showed that insulin resistance (hazard ratio (HR) 2.07; confidence interval (CI) 1.10-3.91, p = 0.024), donor age (HR 1.33;CI 1.08-1.63, p = 0.007) and aspartate aminotransferase (HR 1.03;CI 1.01-1.05, p < 0.001) were significantly associated with a higher probability of developing advanced fibrosis, i.e. Knodell fibrosis stage 3 or 4, whereas steatosis (HR 0.94;CI 0.46-1.92, p = 0.87) and acute cellular rejection (HR 1.72;CI 0.88-3.36, p = 0.111) were not. In conclusion, posttransplant insulin resistance is strongly associated with more severe recurrence of HCV infection. HOMA-IR is an important tool for the identification of insulin resistance among patients at risk for rapid fibrosis progression after liver transplantation for HCV.

Survival in portopulmonary hypertension: Mayo Clinic experience categorized by treatment subgroups.

To determine the natural history of portopulmonary hypertension (POPH), a retrospective screening-right heart catheterization-survival analysis of patients was performed. We categorized patients by three treatment subgroups: (1) no therapy for pulmonary hypertension (PH) or liver transplantation (LT), (2) therapy for PH alone and (3) therapy for PH followed by LT. Seventy-four patients were identified between 1994 and 2007. Nineteen patients received no therapy for PH and no LT representing the natural history of POPH. Five-year survival was 14%, and 54% had died within 1 year of diagnosis. Five-year survival in 43 patients receiving therapy for PH but no LT was 45%, and 12% had died within 1 year of diagnosis. Twelve patients underwent LT and 5-year survival for the nine receiving therapy for PH was 67% versus 25% in the three who were not pretreated with prostacyclin therapy. The survival of untreated patients with POPH was poor. Subgroups of patients selected to medical treatment with or without LT had better long-term survival. Mortality did not correlate with baseline hemodynamic variables, type of liver disease or severity of hepatic dysfunction. Medical therapy for POPH should be considered in all patients with POPH, but the treatment effects and impact on those considered for LT still requires well-designed, prospective study before practice guidelines can be suggested.

Impact of pegylated interferon and ribavirin treatment on graft survival in liver transplant patients with recurrent hepatitis C infection.

Recurrent hepatitis C virus (HCV) infection is a major cause of morbidity and mortality after liver transplantation for HCV-related end stage liver disease. Although previous studies have shown a short-term effect of interferon-based treatment on fibrosis progression, it is unclear whether this translates to improved graft survival. We evaluated whether treatment of recurrent HCV leads to an improved graft survival. Cohort study included consecutive HCV patients who underwent liver transplantation between 1 January 1995 and 1 January 2005 in the Mayo Clinic, Rochester, MN. Two hundred and fifteen patients were included in the study. During a median follow-up of 4.4 years (interquartile range 2.2-6.6), 165 patients (77%) had biopsy-proven recurrent HCV infection confirmed by serum HCV RNA testing. Seventy-eight patients were treated. There were no differences in MELD-score, fibrosis stage or time towards HCV recurrence between treated and untreated patients at time of recurrence. There was a trend for greater frequency of acute cellular rejection among untreated patients. The incidence of graft failure was lower for patients treated within 6 months of recurrence compared to patients not treated within this time-period (log rank p = 0.002). Time-dependent multivariate Cox regression analysis showed that treatment of recurrent HCV infection was statistically significantly associated with a decreased risk of overall graft failure (hazard ratio 0.34; CI 0.15-0.77, p = 0.009) and a decreased risk of graft failure due to recurrent HCV (hazard ratio 0.24; CI 0.08-0.69, p = 0.008). In conclusion, although a cause and effect relationship cannot be established, treatment of recurrent HCV infection after liver transplantation is associated with a reduced risk of graft failure.

Oral cyclosporine decreases severity of neurotoxicity in liver transplant recipients.

Neoral is a new formulation of cyclosporine that permits reliable absorption in patients with external biliary drainage. The authors reviewed 227 liver transplant patients receiving primary treatment with Neoral. Headache occurred in 24 patients (11%), mild tremors in 12 patients, paresthesia in 5 patients, acute confusional state in 4 patients, and seizures in 2 patients. It is apparent that Neoral has profoundly reduced the severity of neurotoxicity in liver transplant recipients.

Neurotoxicity in liver transplant recipients with cyclosporine immunosuppression.

We studied the clinical features, blood levels of cyclosporine, and neuroimaging findings in 46 patients with cyclosporine neurotoxicity after liver transplantation. The clinical presentation of cyclosporine neurotoxicity was characterized by tremulousness and restlessness in all patients and was associated with acute confusional state and psychosis in 20 patients, seizures in eight, speech apraxia or action myoclonus speech in three, and cortical blindness in two. In 35 patients, cyclosporine neurotoxicity occurred during IV treatment. Neuroimaging studies showed only minor white matter abnormalities in two patients despite dramatic clinical presentations, including speech difficulties, seizures, and cortical blindness. In only 19 of 31 patients (61%) did trough levels of cyclosporine suggest neurotoxicity. Neurologic findings were reversible in all patients after cyclosporine was withheld and then given in lower dosage. In three patients, substituting FK 506 did not result in neurotoxicity.

Causes and outcome of seizures in liver transplant recipients.

Previous studies found that seizures in orthotopic liver transplantation (OLT) herald a catastrophic neurologic event, but the studies were done of patients who later died and came to autopsy. We studied 630 OLT patients. Laboratory values, electroencephalography, neuroimaging, and levels of cyclosporine or FK506 were reviewed. Neurotoxicity from immunosuppression was considered a trigger for seizures when toxic blood level or increases > or = to 100% were documented, or when white matter lesions or confusional state or tremors were present. Generalized tonic-clonic seizures occurred in 28 of 630 patients (4%). In 7 patients seizures were part of an agonal event (central nervous system infection [n = 3], anoxic encephalopathy [n = 1], cerebral edema with fulminant hepatic failure [n = 1], intracranial hemorrhage [n = 1], and sepsis [n = 1]. In 17 patients cyclosporine (n = 11) or FK506 (n = 6) could be implicated. Remaining causes were acute uremia (n = 1), meningioma (n = 1), and unknown (n = 2). All patients were initially treated with anticonvulsants. Median follow-up of 2 years did not reveal seizure recurrence after discontinuation of anticonvulsants. We conclude that the majority of new-onset seizures after OLT are not indicative of a poor prognosis. Immunosuppression neurotoxicity is the most frequent cause. Anticonvulsant therapy is not necessary for favorable long-term outcome.

Advances in primary sclerosing cholangitis.

Primary sclerosing cholangitis is an increasingly recognized chronic cholestatic liver disease. It frequently occurs in association with chronic ulcerative colitis and is characterized by inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts. The cause is unknown, although many mechanisms have been considered, including infectious, toxic, and immunologic. The prognosis varies. No adequate treatment exists, although a number of potential treatments have been evaluated in uncontrolled trials, and the results of controlled trials have only recently been reported. Liver transplantation has recently been shown to be an effective treatment for end-stage disease. These various advances in our understanding of primary sclerosing cholangitis are reviewed.

A long-term comparison of tacrolimus (FK506) versus cyclosporine in liver transplantation: a report of the United States FK506 Study Group.

BACKGROUND: The long-term (5 year) efficacy and safety of tacrolimus (FK506) and cyclosporine were compared in primary liver transplant recipients who participated in a 1-year randomized, multicenter trial and a 4-year follow-up extension study. METHODS: A total of 529 patients (263 tacrolimus group, 266 cyclosporine group) were randomized to study drug. Patients were evaluated at 3-month intervals. Patient and graft survival rates, incidence of adverse events, and changes in laboratory and clinical profiles were determined. RESULTS: Cumulative 5-year patient and graft survival rates were comparable for the tacrolimus (79.0%, 71.8%) and cyclosporine (73.1%, 66.4%) groups. However, patient half-life survival was longer for tacrolimus-treated patients (25.1+/-5.1 years versus 15.2+/-2.5 years; P=0.049). Improved patient survival with tacrolimus was also observed for hepatitis C-positive patients (78.9% tacrolimus group versus 60.5% cyclosporine group; P=0.041). Both treatments were associated with a low incidence of late acute rejection, late steroid-resistant rejection, and death or graft loss related to rejection. Both treatments demonstrated an acceptable safety profile with maintenance of adequate renal and liver function and a low incidence of malignancy/lymphoproliferative disease and serious infections. CONCLUSIONS: Tacrolimus is a safe and effective long-term maintenance immunosuppressive agent in primary liver transplantation.

Safety and efficacy of hepatitis A vaccination in liver transplantation recipients.

OBJECTIVE: Vaccination against hepatitis A (HAV) has been shown to be safe and effective in healthy subjects and in patients with chronic liver disease (CLD). The safety and efficacy of HAV vaccines in liver transplant (OLT) recipients have not been established. The objective of this study is to assess the safety and efficacy of inactivated hepatitis A vaccine in OLT recipients. METHODS: Thirty-seven HAV seronegative OLT recipients were enrolled. Patients received two doses of vaccine 6 months apart. Postvaccination IgG anti-HAV were determined at 1, 6, and 7 months after the first vaccine dose. Side effects were monitored for 3 days after each vaccination shot. An unvaccinated control group (45 patients) was followed for evidence of seroconversion. Seroconversion rate was also compared with those reported in healthy patients and in patients with chronic liver disease. RESULTS: Testing was available for all the cases at 1 month, and for 26 and 23 patients at 6 and 7 months, respectively. Only 3 of 37 patients (8%) had seroconversion at 1 month. At 6- and 7-month time points, 5 of 26 (19%) and 6 of the 23 (26%) patients had seroconversion, respectively. Vaccine responders had higher total white blood cell count and lymphocyte count and were further out from transplant compared with nonresponders. None of the unvaccinated patients had seroconversion over the follow-up time. Seroconversion rates in OLT recipients were significantly lower than that reported in healthy individuals (P=0.001) or in pre-OLT patients with CLD (P=0.001). All patients tolerated the vaccine well. CONCLUSIONS: HAV vaccination is safe in OLT recipient. Efficacy of HAV vaccination in OLT recipients, as measured by a commercially available enzyme immunoassay, is low and alternative strategies should be developed to improve response rate.

Enhanced liver calpain protease activity is a risk factor for dysfunction of human liver allografts.

Our aim was to determine whether calpain protease activity is increased in liver tissue from allografts that have poor graft function postoperatively. Liver tissue was obtained from 36 patients at 1 hr after recirculation. The patients were divided into two groups: (1) 30 patients with good graft function; and (2) six patients with immediate poor graft function. Calpain protease activity was increased 1.6-fold in biopsy specimens from patients with immediate poor function as compared with those with excellent graft function. There was no difference between the two groups with regard to cold ischemic time for organ storage, donor age, recipient age, United Network for Organ Sharing status of the recipient, or fatty infiltration of the donor liver. In summary, enhanced calpain protease activity present in the liver 1 hr after reperfusion is a risk factor for graft dysfunction.

Cytomegalovirus and its association with hepatic artery thrombosis after liver transplantation.

BACKGROUND: Hepatic artery thrombosis (HAT) is a cause of morbidity and graft loss in approximately 7% of patients after an orthotopic liver transplantation (OLT). Although technical problems are often thought to be the cause of HAT, in general the etiology remains unclear. Because cytomegalovirus (CMV) can infect endothelial cells in vitro and lead to a rapid procoagulant response, it can be hypothesized that, in the absence of CMV antibodies, latent CMV in an allograft may become activated and promote or contribute to vascular thrombosis. Therefore, the purpose of this study was to examine the relationship between CMV serology of the donor and recipient with the development of HAT after OLT. METHODS: Between July 1988 and November 1995 (University of Wisconsin era), 490 OLTs were performed in 413 patients. Subsequently, four patients were excluded in whom the CMV serology results of the donor were not available. Sixteen of the 409 patients developed HAT within 30 days after liver transplantation. The control group consisted of the other 393 patients. RESULTS: The incidence of HAT was 12.5% in 64 CMV D+R- patients and 0% in 52 CMV D-R- patients. However, in the other combinations (D+R+ and D-R+), the incidence was only 2.8% (P = 0.005). Eight of the 16 patients with HAT belonged to the CMV D+R- group. CONCLUSIONS: We conclude that CMV-seronegative patients receiving a seropositive allograft may be at risk for early HAT. Seropositivity of the donor alone and of the recipient alone was not significantly related to the incidence of HAT. Prophylactic treatment with ganciclovir and/or anticoagulation should be evaluated to prevent this complication.

Splenic artery aneurysms in liver transplant patients.

We found splenic artery aneurysms in 6 of 71 consecutive patients who underwent orthotopic liver transplantation at the Mayo Clinic. The incidence of splenic artery aneurysms in cirrhotic patients with portal hypertension was 10%. Five of the aneurysms were found in patients suffering from chronic active hepatitis, whereas no aneurysms were encountered in patients with primary sclerosing cholangitis or primary biliary cirrhosis. One patient ruptured a splenic artery aneurysm shortly after liver transplantation, and 1 patient developed an aneurysm 3 months after transplantation. We recommend coeliac angiography to be performed prior to liver transplantation, and if splenic artery aneurysms are found, ligation of the splenic artery should be performed at the time of transplantation to prevent possible rupture.

Elevation of plasma endothelin associated with systemic hypertension in humans following orthotopic liver transplantation.

Endothelin (ET) is a 21-amino-acid peptide of endothelial origin, is a potent systemic and renal vasoconstrictor associated with sodium retention and modulation of the renin-angiotensin-aldosterone system. The present study was designed to determine if plasma ET is elevated in humans with cirrhosis (n = 12), a state characterized by sodium retention and increased plasma renin activity (PRA) and plasma aldosterone (PA), and to determine the effect of orthotopic liver transplantation (OLT) upon plasma ET, PRA, and PA at 1, 3, and 7 days after transplantation. Plasma ET before OLT was 1.62 +/- 0.23 pg/ml, which was not different as compared with normal controls. Plasma ET significantly increased to 4.18 +/- 0.66, 3.87 +/- 0.58, and 4.07 +/- 0.61 pg/ml, respectively following OLT. PRA remained elevated throughout the postoperative course, in contrast to PA that decreased following OLT. Mean arterial pressure increased significantly from 82 +/- 4 pre-OLT to 98 +/- 4 and 103 +/- 2 mmHG on days 3 and 7 respectively.

The impact of immunosuppressive regimens on the cost of liver transplantation--results from the U.S. FK506 multicenter trial.

In an effort to determine the total one-year cost of liver transplantation, the underlying drivers of that cost, and any cost differences between alternative immunosuppressive regimens, an analysis was performed comparing the average one-year posttransplant charges of 322 patients participating in the "U.S. Multi-center Prospective Randomized Trial Comparing FK-506 to Cyclosporine in Liver Transplantation." Total one-year inpatient charges including all readmissions were examined. Professional fees and outpatient charges were excluded. Costs for tacrolimus drug and blood assays were assumed to be equal to those in the CsA group. For patients completing the study, the tacrolimus group had an average length of stay and average one-year cost seven days (P = .06) and $19,290 (P = .05) lower than the CsA group. The difference in rejection profiles between the two arms seems to largely account for the lower costs. The tacrolimus arm consistently had fewer patients in the more severe rejection groups. Increased incidence and severity of rejection were directly related to higher average lengths of stay and costs of transplantation (P < .001). Tacrolimus immunosuppression during the first year after liver transplantation is more cost-effective than CsA in achieving similar patient and graft survival rates. Differing incidence and severity of rejection can dramatically affect the first-year cost of liver transplantation.

Use of fatty donor liver is associated with diminished early patient and graft survival.

It is well known that implantation of donor livers with severe fatty infiltration (>60%) is frequently associated with early hepatic dysfunction and an increased incidence of primary nonfunction after liver transplantation. The outcome of donor livers with less fatty infiltration has not been well defined. We, therefore, studied the outcome of 59 liver transplantations in which donor livers with up to 30% fat were used. Patient outcome was compared to a time-matched control group of 57 patients. The two groups were similar in terms of age, gender, preservation time, primary diagnosis, and UNOS status. We compared both groups with regard to 4-month and 2-year patient and graft survival. We also assessed the incidence of ischemic type biliary strictures and hepatic artery thrombosis, and evaluated the causes of graft loss in both groups. We found that use of donor livers with up to 30% fatty infiltration was associated with a significant decrease in 4-month graft survival (76% vs. 89%, P<0.05) and in 2-year patient survival (77% vs. 91%, P<0.05). Primary nonfunction and primary dysfunction formed the main cause of graft loss and mortality. Multivariate analysis showed that fatty infiltration is an independent predictive factor for outcome after transplantation. We conclude that liver allografts with up to 30% fat lead to diminished outcome after liver transplantation. However, this diminished outcome should be viewed with respect to the increasing mortality on the national waiting list.

Hepatitis G virus infection in patients transplanted for cryptogenic cirrhosis: red flag or red herring?

BACKGROUND: The significance of hepatitis G (HGV) infection in liver transplant recipients is not known. We set out to determine the pre-orthotopic liver transplantation (OLT) prevalence, the pre- and postoperative viral titers of HGV, and the allograft histology in patients infected with HGV who underwent OLT for cryptogenic cirrhosis. METHODS: HGV RNA was measured using a research-based branched DNA assay. The assay used a target-specific probe set that was based on the 5'-untranslated region of the HGV genome. Allograft histology was assessed with protocol liver biopsies in all patients who survived longer than 6 months. RESULTS: The preoperative prevalence of HGV infection in recipients transplanted for cryptogenic cirrhosis was 26%. Thirty-seven percent (12 of 33) of recipients who had serum available in the first postoperative month had HGV infection. Mean HGV RNA levels were 9.8 (+/-4.2) (viral molecular equivalents/ml x 10[6]) before OLT and 37.5 (+/-10.7) at 1 year after OLT. In 4 of the 11 cryptogenic recipients in whom HGV RNA was detectable in the first postoperative month, HGV RNA fell to undetectable levels at the most recent follow-up (mean 70 months). Of the five cryptogenic recipients who continue to have measurable HGV RNA, three have unexplained hepatitis histologically. CONCLUSIONS: These findings suggest the following: 1) The prevalence of HGV infection in patients undergoing OLT for cryptogenic cirrhosis is about 25%. 2) In recipients persistently infected with HGV, mean HGV RNA titers increase after OLT. 3) HGV RNA becomes undetectable in about one third of recipients who had detectable HGV RNA in the first month after OLT. 4) Hepatitis of uncertain etiology occurs in 60% (3 of 5) of persistently HGV-infected cryptogenic recipients.

Role of steroid dose in hypertension early after liver transplantation with tacrolimus (FK506) and cyclosporine.

Transplant immunosuppression using either cyclosporine (CsA) or tacrolimus (FK506) leads to renal vasoconstriction and nephrotoxicity. Despite producing similar effects within the kidney and blood vessels, clinical hypertension occurs less frequently with tacrolimus during the first year after transplantation, compared with CsA. To examine the role of steroid dose in early posttransplant hypertension, we measured blood pressure and kidney function in liver transplant recipients treated with tacrolimus and either high-dose (TAC-HI-P, n = 19) or low-dose (TAC-LO-P,n = 20) prednisone, compared with CsA-treated recipients (n = 29) receiving prednisone doses similar to the TAC-HI-P group. At 1 month, hypertension occurred more often with CsA (72%) than with TAC-HI-P (42%, P < 0.05) or TAC-LO-P (30%, P < 0.05). By 4 months after transplantation, hypertension developed in nearly twice as many TAC-HI-P (63%) as TAC-LO-P patients (32%, P < 0.05), with no difference between TAC-HI-P and CsA (86%, NS). Daily prednisone dose at 1 month closely paralleled cumulative steroid dose in the first month in the TAC-HI-P and TAC-LO-P groups. Fourteen of 19 TAC-HI-P patients (74%) required bolus steroids for treatment of rejection within the first month, compared with 3/20 (15%) TAC-LO-P and 10/29 (34%) CsA recipients. Glomerular filtration rate fell from pretransplant levels at 1 month and 4 months to the same degree in CsA, TAC-HI-P, and TAC-LO-P patients. These results demonstrate a central role for steroid dose in the rate of onset of hypertension early after liver transplantation using tacrolimus immunosuppression. Both daily dose and cumulative dosage, including bolus treatment for rejection, may impact on the development of hypertension. Since prevalence rates rise to levels comparable to CsA by 24 months regardless of steroid dose, hypertension after liver transplant may be mediated by different mechanisms at different stages of the posttransplant course.