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Background: Because of the spectrum of intrapulmonary vascular dilation that characterizes hepatopulmonary syndrome (HPS), PaO(2) while breathing 100% oxygen varies. Abnormal extrapulmonary uptake of (99m)Tc macroaggregated albumin (MAA) after lung perfusion is common.Goal: To describe relationships between (1) severity of liver disease measured by the Child-Pugh (CP) classification; (2) PaO(2) while breathing room air (RA) and 100% oxygen on 100% oxygen; and (3) extrapulmonary (brain) uptake of (99m)Tc MAA after lung scanning.Methods and Patients: We prospectively measured PaO(2) on RA, PaO(2) on 100% oxygen, and brain uptake after lung perfusion of (99m)Tc MAA in 25 consecutive HPS patients.Results: Mean PaO(2) on RA, PaO(2) on 100% oxygen, PaCO(2) on RA, and (99m)Tc MAA brain uptake were similar when categorized by CP classification. Brain uptake was abnormal (> or = 6%) in 24 patients (96%). Brain uptake was 29 +/- 20% (mean +/- SD) and correlated inversely with PaO(2) on RA (r = -0.57; p<0.05) and PaO(2) on 100% oxygen (r = -0.41; p<0.05). Seven patients (28%) had additional nonvascular pulmonary abnormalities and lower PaO(2) on 100% oxygen (215+/-133 mm Hg vs 391+/-137 mm Hg; p<0.007). Eight patients (32%) died. Mortality in patients without coexistent pulmonary abnormalities was associated with greater brain uptake of (99m)Tc MAA (48+/-18% vs 25+/-20%; p<0.04) and lower PaO(2) on RA (40+/-7 mm Hg vs 57+/-11 mm Hg; p<0.001).Conclusion: The degree of hypoxemia associated with HPS was not related to the CP severity of liver disease. HPS patients with additional nonvascular pulmonary abnormalities exhibited lower PaO(2) on 100% oxygen. Mortality was associated with lower PaO(2) on RA, and with greater brain uptake of (99m)Tc MAA. [ABSTRACT FROM AUTHOR]

We reviewed the records of 20 liver transplant patients who underwent 28 procedures [endoscopic retrograde cholangiopancreatography (ERCP)] to rule out biliary obstruction, treat bile leaks, dilate and/or stent strictures, or remove stones and debris. Three patients (two with abnormal T-tube cholangiograms and one with hyperbilirubinemia) underwent ERCP to rule out obstruction. Therapeutic ERCP (sphincterotomy with balloon dilatation or stone extraction) was successful in 16 of 17 patients, including seven of nine in whom there was resolution of bile leaks without the use of stents or surgery. Mild pancreatitis occurring in one patient was the only complication experienced that was related to ERCP. We conclude that ERCP is a safe and important modality in the medical management of biliary tract complications after orthotopic liver transplantation. [ABSTRACT FROM AUTHOR]

Background: The vasoconstrictor terlipressin is used for type 1 hepatorenal syndrome (HRS-1) in many parts of the world and is part of the clinical practice guidelines in Europe.Methods: We conducted a phase 3 trial to confirm the efficacy and safety of terlipressin plus albumin in adults with HRS-1. The patients were randomly assigned in a 2:1 ratio to receive terlipressin or placebo for up to 14 days; in both groups, concomitant use of albumin was strongly recommended. The primary end point was verified reversal of HRS, defined as two consecutive serum creatinine measurements of 1.5 mg per deciliter or less at least 2 hours apart and survival without renal-replacement therapy for at least 10 days after the completion of treatment. Four prespecified secondary end points were analyzed with the Hochberg procedure to account for multiple comparisons.Results: A total of 300 patients underwent randomization - 199 were assigned to the terlipressin group and 101 to the placebo group. Verified reversal of HRS was reported in 63 patients (32%) in the terlipressin group and 17 patients (17%) in the placebo group (P = 0.006). With respect to the prespecified secondary end points, HRS reversal, defined as any serum creatinine level of 1.5 mg per deciliter or less during the first 14 days, was reported in 78 patients (39%) in the terlipressin group and 18 (18%) in the placebo group (P<0.001); HRS reversal without renal-replacement therapy by day 30, in 68 (34%) and 17 (17%), respectively (P = 0.001); HRS reversal among patients with systemic inflammatory response syndrome (84 patients in the terlipressin group and 48 patients in the placebo group), in 31 (37%) and 3 (6%), respectively (P<0.001); and verified reversal of HRS without recurrence by day 30, in 52 (26%) and 17 (17%), respectively (P = 0.08). At day 90, liver transplantations had been performed in 46 patients (23%) in the terlipressin group and 29 patients (29%) in the placebo group, and death occurred in 101 (51%) and 45 (45%), respectively. More adverse events, including abdominal pain, nausea, diarrhea, and respiratory failure, occurred with terlipressin than with placebo. Death within 90 days due to respiratory disorders occurred in 22 patients (11%) in the terlipressin group and 2 patients (2%) in the placebo group.Conclusions: In this trial involving adults with cirrhosis and HRS-1, terlipressin was more effective than placebo in improving renal function but was associated with serious adverse events, including respiratory failure. (Funded by Mallinckrodt Pharmaceuticals; CONFIRM ClinicalTrials.gov number, NCT02770716.). [ABSTRACT FROM AUTHOR]

Ascites is a common complication of cirrhosis, and heralds a new phase of hepatic decompensation in the progression of the cirrhotic process. The development of ascites carries a significant worsening of the prognosis. It is important to diagnose noncirrhotic causes of ascites such as malignancy, tuberculosis, and pancreatic ascites since these occur with increased frequency in patients with liver disease. The International Ascites Club, representing the spectrum of clinical practice from North America to Europe, have developed guidelines by consensus in the management of cirrhotic ascites from the early ascitic stage to the stage of refractory ascites. Mild to moderate ascites should be managed by modest salt restriction and diuretic therapy with spironolactone or an equivalent in the first instance. Diuretics should be added in a stepwise fashion while maintaining sodium restriction. Gross ascites should be treated with therapeutic paracentesis followed by colloid volume expansion, and diuretic therapy. Refractory ascites is managed by repeated large volume paracentesis or insertion of a transjugular intrahepatic portosystemic stent shunt (TIPS). Successful placement of TIPS results in improved renal function, sodium excretion, and general well-being of the patient but without proven survival benefits. Clinicians caring for these patients should be aware of the potential complications of each treatment modality and be prepared to discontinue diuretics or not proceed with TIPS placement should complications or contraindications develop. Liver transplantation should be considered for all ascitic patients, and this should preferably be performed prior to the development of renal dysfunction to prevent further compromise of their prognosis.

To determine the frequency, risk factors, and consequences of recurrent autoimmune hepatitis after liver transplantation, 41 patients with type 1 disease were monitored after surgery in accordance with a surveillance protocol. Tacrolimus or cyclosporine plus prednisone were administered to each patient, and liver biopsy examinations were performed at least annually according to protocol. Corticosteroid therapy was ultimately discontinued in only 2 patients. Recurrent disease was defined as the presence of lymphoplasmacytic infiltrates in liver tissue in the absence of other causes of allograft dysfunction. Autoimmune hepatitis recurred in 7 patients (17%), and the mean time to recurrence was 4.6 +/- 1 years. Recurrence was asymptomatic in 4 of 7 patients and detected only by surveillance liver biopsy assessment in 2 patients. Histological changes were mild, and there was no progression to cirrhosis during 4.9 +/- 0.9 years of observation. Five-year patient (86% v. 82%; P =.9) and graft (86% v. 67%; P =.5) survival rates were not statistically different between patients with and without recurrent disease. HLA-DR3 or HLA-DR4 occurred more commonly in patients with than without recurrence (100% v. 40%; P =.008) and healthy subjects (100% v. 49%; P =.01). Recurrent disease was unrelated to donor HLA status. In conclusion, recurrence after transplantation for type 1 autoimmune hepatitis is common. Its mild manifestations and favorable prognosis may reflect early detection by a surveillance protocol and/or continuous corticosteroid treatment. HLA-DR3- or HLA-DR4-positive recipients are at risk for recurrence regardless of donor HLA status.

Protein-calorie malnutrition, best measured by body cell mass (BCM) depletion, has been associated with adverse outcomes in patients with end-stage liver disease. We prospectively measured BCM and multiple standard nutritional parameters in patients with end-stage liver disease to determine which, if any, of the traditionally measured nutritional parameters correlate with BCM. A detailed nutritional assessment, including BCM analysis, subjective global assessment, anthropometry, handgrip dynamometry, laboratory tests, and body composition measured by dual-energy X-ray absorptiometry was performed in 69 sequential patients awaiting liver transplantation. The frequency of abnormalities of specific parameters of nutritional status varied between 19% and 99%. Most of the commonly measured parameters of nutritional status correlated poorly with BCM. Patients with depleted BCM (lowest quartile for sex) had midarm circumference (P <.01), arm-muscle circumference (P <.001), handgrip strength (P <.001), blood urea nitrogen (P <.01), and creatinine (P <.01) values less than those for patients with greater BCM (highest 3 quartiles for sex). In multivariate analysis, arm-muscle circumference and handgrip strength were the best predictors of BCM. The combined criteria of handgrip strength less than 30 kg and arm-muscle circumference less than 23 cm have a sensitivity of 94% and a negative predictive value of 97% in identifying patients with depleted BCM. Although abnormalities of nutritional parameters are highly prevalent among patients with end-stage liver disease, most parameters of nutritional status do not correlate with BCM. In patients with end-stage liver disease, arm-muscle circumference and handgrip strength are the most sensitive markers of BCM depletion.

Nuclear factor kappaB (NF-kappaB) is activated during viral infection and is central to the regulation of host immune responses. The NF-kappaB activation status and its morphological sources were assessed by immunohistochemistry in allograft biopsy specimens of orthotopic liver transplantation patients with recurrent hepatitis C virus (HCV). Hepatocellular NF-kappaB immunostaining was detected in HCV cases compared with controls (nontransplant: P <.001; transplant: P =.006), which correlated with the number of NF-kappaB positive hepatocytes (P =.007) and contrasted to the absent to weak staining of controls (nontransplant: P =.001; transplant: P =.009). Enhanced NF-kappaB staining of cytokeratin 19-positive bile ducts and proliferating ductules in the HCV group was in contrast to controls. Intense NF-kappaB immunoreactivity was detected in CD68-positive Kupffer cells and macrophages of all HCV specimens compared with a few controls (nontransplant: P <.001; transplant: P =.001) and contrasted to the weak staining of controls (nontransplant: P <.001; transplant: P =.001). NF-kappaB-positive immunoreactivity correlated with the number of T cell receptor (TCR) alpha/beta-positive lymphocytes (P <.001), which was not observed in controls. In those HCV cases showing evidence of necroinflammatory activity (grade) and individual features of portal inflammation, periportal inflammation/piecemeal necrosis, lobular inflammation, and fibrosis (stage), higher NF-kappaB staining intensity scores within bile ducts, proliferating ductules, hepatocytes (piecemeal necrosis: P =.016; stage: P =.030), and lymphocytes (stage: P =.044) and increased number of NF-kappaB-positive cells within bile ducts, proliferating ductules (grade, lobular inflammation, piecemeal necrosis, stage: P =.022), hepatocytes, and lymphocytes were observed. Increased staining intensity and frequency of NF-kappaB-positive cells were similarly observed in HCV-positive allografts obtained from patients under tacrolimus- compared with cyclosporine-based immunosuppression. These data implicate an immunoregulatory role of intragraft NF-kappaB activation in the pathogenesis and progression of posttransplantation HCV disease recurrence.

Background: We studied the economic impact of cytomegalovirus (CMV) disease and its effective reduction with antiviral prophylaxis in liver transplant recipients., Method: Analysis of institutional charge data accumulated during a prospective, randomized, controlled trial comparing oral acyclovir 800 mg four times daily for 120 days (ACV) and intravenous ganciclovir 5 mg/kg every 12 h for 14 days followed by ACV for 106 days (GCV) was performed., Results: Liver transplant recipients who developed CMV disease had significantly higher charges (median: $148,300) than those who developed asymptomatic CMV infection ($119,600) or experienced no CMV infection ($114,100) (P<0.01). A multiple linear regression analysis indicated that CMV disease is associated with a 49% increase in charges, independent of other factors influencing increased hospitalization charges. In CMV-seronegative patients who received a CMV-seropositive donor organ, GCV prophylaxis was associated with a significant reduction in charges, as compared to ACV prophylaxis ($113,900 vs. $153,300, respectively; P=0.02)., Conclusions: CMV disease is an independent risk factor for increased resource utilization associated with liver transplantation. The use of an effective prophylactic antiviral regimen provides savings in health care resources, particularly in patients at high risk for developing CMV disease.

Previously, we found appreciable hepatic iron deposition in one third of our patients undergoing liver transplantation (LTx) with approximately 10% of cases having quantifiable iron in the range of that seen in hereditary hemochromatosis (HHC). The aim of this study was to compare clinical outcome in liver transplant patients with and without iron overload. We also sought to determine the prevalence of HFE mutations in liver transplant patients with iron overload. Of 456 consecutive liver transplants, 41 explants had an hepatic iron index (HII) greater than 1.9, and these cases were compared to 41 matched liver transplant recipients without increased hepatic iron. Posttransplantation complications, along with patient and graft survival were monitored. HFE gene testing was performed using DNA-based techniques. Kaplan-Meier 5-year patient survival after LTx was significantly lower in cases with hepatic iron overload compared to matched controls without iron excess (48% vs. 77%; P =.045). Fatal infections (especially fungal) were more common in patients with iron overload (24% vs. 7%; P =.03). Of the 41 patients with a liver explant HII greater than 1.9, only 4 were C282Y homozygotes. Patients with severe hepatic explant iron overload undergoing LTx have a reduced survival compared to liver transplant recipients without explant iron excess. The reduced survival was attributable mainly to fatal bacterial and fungal infections. Despite the iron overload, HFE gene mutations were uncommon in patients with hepatic explant hemosiderosis.

Liver transplantation is the only effective therapeutic option for patients with end-stage liver disease due to primary sclerosing cholangitis (PSC). In this study, we analyzed a single center's experience with 150 consecutive PSC patients who received 174 liver allografts. Mean follow-up was 55 months. Actuarial patient survival at 1, 2, 5, and 10 years was 93.7%, 92.2%, 86.4%, and 69.8%, respectively, whereas graft survival was 83.4%, 83.4%, 79.0%, and 60. 5%, respectively. The main indication for retransplantation was hepatic artery thrombosis, and the major cause of death was severe infection. Patients with PSC had a higher incidence of acute cellular and chronic ductopenic rejection compared to a non-PSC control group. Chronic ductopenic rejection adversely affected patient and graft survival. Biliary strictures, both anastomotic and nonanastomotic, were frequent and occurred in 16.2% and 27.2% of patients, respectively. The incidence of recurrent PSC was 20%. A negative impact on patient survival was not seen in patients with either postoperative biliary strictures or recurrence of PSC. Six patients (4%) had cholangiocarcinoma and 1 patient died related to recurrence of malignant disease. Seventy-eight percent of PSC patients had associated inflammatory bowel disease, most commonly chronic ulcerative colitis, which did not adversely impact patient outcome posttransplantation. Nine patients required proctocolectomy after liver transplantation; 5 because of intractable symptoms related to inflammatory bowel disease and 4 due to the development of colorectal carcinoma/high-grade dysplasia. Our data show that liver transplantation provides excellent long-term patient and graft survival for patients with end-stage PSC.

Patients with end-stage liver failure, portal hypertension, and associated pulmonary artery hypertension (portopulmonary hypertension [PPHTN]) have a high mortality when undergoing liver transplantation. Successful transplantation in these patients may depend on efforts to reduce pulmonary artery pressure (PAP). To this end, a number of centers are using a continuous intravenous (IV) infusion of epoprostenol, which has been shown to improve symptoms, extend life span, and reduce PAP in patients with primary pulmonary hypertension. We report four cases in which treatment of patients with PPHTN with continuous IV epoprostenol was followed by the development of progressive splenomegaly, with worsening thrombocytopenia and leukopenia. This finding may limit the usefulness of epoprostenol in PPHTN and influence the timing of transplantation in such patients.

Recurrence of primary sclerosing cholangitis (PSC) following liver transplantation has been suggested; however, it has not been fully defined because of numerous complicating factors and the lack of diagnostic criteria. In the present study, we investigated the recurrence of PSC by developing strict criteria and applying them to a large cohort of PSC patients who underwent liver transplantation. Between March 1985 and June 1996, 150 PSC patients underwent liver transplantation at the Mayo Clinic; mean follow up was 55 months. The incidence of nonanastomotic biliary strictures and hepatic histologic findings suggestive of PSC were compared between patients transplanted for PSC and a non-PSC transplant control group. Our definition of recurrent PSC was based on characteristic cholangiographic and histologic findings that occur in nontransplant PSC patients. By using strict criteria, 30 patients with other known causes of posttransplant nonanastomotic biliary strictures were excluded leaving 120 patients for analysis of recurrence of PSC. We found evidence of PSC recurrence after liver transplantation in 24 patients (20%). Of these, 22 out of 24 patients showed characteristic features of PSC on cholangiography and 11 out of 24 had compatible hepatic histologic abnormalities with a mean time to diagnosis of 360 and 1,350 days, respectively. Both cholangiographic and hepatic histologic findings suggestive of PSC recurrence were seen in nine patients. The higher incidence and later onset of nonanastomotic biliary strictures in patients with PSC compared with a non-PSC control group is supportive of the fact that PSC does recur following liver transplantation. We were unable to identify specific clinical risk factors for recurrent PSC, and the overall patient and graft survival in patients with recurrent PSC was similar to those without evidence of recurrence. Our observations provide convincing evidence that PSC frequently recurs in the hepatic allograft using strict inclusion and exclusion criteria.

The CD40-CD40L (CD154) interaction plays a pivotal role in the effector mechanisms of allograft rejection. Blockade of the CD40/CD40L costimulatory pathway prevents the development of chronic allograft rejection in several animal transplant models. The relevance of in situ CD40 and CD40L expression in human liver allografts was assessed by immunohistochemistry during ductopenic chronic rejection (CR). In CR allograft specimens (n = 8), marked CD40L expression was detected on Kupffer cells (KCs) and sinusoidal macrophages with a unique centrilobular distribution (P <.001). The CD40L+ KCs and macrophages were shown to be CD68+ after immunohistochemical analysis of serial sections with anti-CD68 monoclonal antibody. Moderate staining of vascular and sinusoidal endothelial cells and mononuclear infiltrates was observed in some CR cases. These findings were in contrast to the absence of CD40L expression in controls (n = 11) consisting of stable liver allograft and normal liver tissue specimens. Only occasional CD40 expression in some cases of CR and controls was observed. In CR, CD40L (CD154) expression is manifested on KCs and macrophages. The present novel data show another important cellular source of CD40L expression and suggest a potential role of KCs/macrophages and CD40/CD40L costimulatory interactions in the pathogenesis of chronic rejection ductopenic liver allograft.

Controversy exists whether patients who are genetically heterozygous for 1-antitrypsin deficiency (1ATD), carrying a single PI*Z allele, are at increased risk of developing chronic liver disease. In these investigations, we determined the prevalence of heterozygous 1AT phenotypes (PI MZ, PI SZ) in a well-characterized cohort of patients presenting with chronic liver failure before orthotopic liver transplantation (OLT). We analyzed data collected from all adult patients (n = 641) who underwent OLT at our tertiary referral center between March 1985 and December 1996. Study patients entered a prospective protocol designed to test for all known etiologies of liver disease. Complete testing including 1AT phenotyping was successfully performed in 599 adults. We compared the overall number of heterozygous PI*Z carriers in our OLT cohort with established prevalence figures for general and regional American populations, and examined their distribution among various liver disease subgroups. Fifty-one patients were found to be heterozygous carriers of a single PI*Z allele for 1AT. The predominant phenotype in our transplantation cohort was PI MZ, identified in 49 patients (8.2%), which is a significantly higher prevalence than that reported from previous American population studies (2%-4%). Additionally, a significantly greater number of PI MZ carriers existed in patients with cryptogenic cirrhosis compared with other liver disease categories (26.9%; P < .001). These data suggest that individuals carrying a single PI*Z allele for 1AT may be at increased risk of developing cirrhosis and liver failure, even in the absence of an identifiable coexisting liver disease.

Neoral is a new formulation of cyclosporine based on microemulsion technology, designed to provide increased and more reliable absorption of the medication. The aim of this study was to assess whether conversion from Sandimmune to Neoral provides safe and effective oral immunosuppression in stable liver transplant recipients. We studied 59 stable liver transplant recipients (being treated with prednisone, azathioprine, and Sandimmune). All patients were enrolled in an open-label study in which they were converted from Sandimmune to Neoral therapy at a dose ratio of 1:1. Thirty-nine patients underwent duct-to-duct bile duct anastomoses, and 20 underwent Roux-en-Y bile duct anastomoses. After conversion, the Neoral dosage was adjusted on the basis of trough levels measured at weeks 1, 2, 3, 4, 6, 8, and 12. To assess safety and tolerability, we prospectively obtained serial information, including laboratory data and information on side effects. Standard statistical methodology was used. A total of 59 patients (23 men, 36 women; mean age, 55 years; mean follow-up after liver transplantation, 5.7 years) completed 3 months of follow-up after conversion from Sandimmune to Neoral. There were 32 dosage changes; 22 (69%) required reduction of the Neoral dose. Mean cyclosporine trough levels remained above 100 ng/mL during the follow-up period. There were no significant differences between cyclosporine levels in patients with duct-to-duct or Roux-en-Y bile duct anastomoses. There were no episodes of rejection during the 3-month follow-up period. The side effect profile was similar in both groups, except for a significant reduction in the number of patients with headaches after Neoral conversion. Liver transplant recipients can safely be converted from Sandimmune to Neoral. Neoral was well tolerated in this population.

In 1989, we reported on the efficacy of liver transplantation in primary biliary cirrhosis (PBC) by demonstrating that the actual patient survival following transplantation was significantly better than without transplantation as predicted by a mathematical survival model ("Mayo natural history model"). Our aim in this investigation was to determine an optimal time to perform liver transplantation in PBC. One hundred forty-three patients with PBC undergoing liver transplantation were followed prospectively. Disease severity was measured immediately before transplantation by a summary score ("risk score") used in the Mayo natural history model, namely age, bilirubin, albumin, prothrombin time, and the presence or absence of edema. Proportional hazards analyses were performed assessing patient survival following transplantation. The influence of disease severity immediately pretransplantation on resource utilization for liver transplantation was assessed. Compared with our report in 1989, liver transplantation was performed at an earlier stage of disease (e.g., median risk score: 7.5 vs. 8.3; P < .01). Following transplantation, patient survival probabilities at 1, 2, and 5 years were 93%, 90%, and 88%, respectively. In the proportional hazards analysis, the risk of death following transplantation remained low until reaching a risk score of 7.8. In contrast, risk scores greater than 7.8 were associated with a progressively increased mortality. Resource utilization measured by the days in the intensive care unit (ICU) and hospital and the requirement for intraoperative blood transfusions was significantly greater in recipients who had higher risk scores before transplantation. Our data suggest that an optimal timing for liver transplantation, as determined by patient survival and resource utilization, appears to be at a risk score around 7.8 in patients with PBC.

Hypertension frequently develops early after liver transplantation when cyclosporine-based immunosuppression is used. However, initial experience with tacrolimus has suggested that its use leads to a lower early incidence of hypertension. In this study, the blood pressure status of patients treated with cyclosporine (n = 131) and those treated with tacrolimus (n = 28) was compared 24 months after liver transplantation. At this time interval, the prevalence of hypertension in the cyclosporine and tacrolimus groups were 82% and 64%, respectively (P < .05). For those patients who were hypertensive by 24 months, onset was delayed in the tacrolimus group compared with the cyclosporine group: 40% versus 71% and 73% versus 93% at 1 and 12 months, respectively (P < .05). Within the cyclosporine group, patients with hypertension were heavier than those with normal blood pressure, 84.7 +/- 1.8 versus 73.4 +/- 4.0 kg, respectively (P < .05). Within the tacrolimus group, hypertensive patients had lower glomerular filtration rates and higher renal vascular resistances compared with normotensive patients, 74 +/- 12 versus 47 +/- 6 mL/min and 15,711 +/- 2,445 versus 28,830 +/- 4,310 dyne/s/cm5/m2, respectively (P < .05). There were no within-group differences for age, gender, pretransplant history of hypertension, family history of hypertension, graft function, or daily doses of prednisone, cyclosporine, or tacrolimus. These results indicate that, compared with cyclosporine, the onset of hypertension after liver transplantation is delayed and less prevalent with tacrolimus. Additionally, hypertension is associated with increased body weight in cyclosporine-treated patients and with more severe renal dysfunction in patients receiving tacrolimus. The relationships of these findings to the development of posttransplant hypertension requires further study., (Copyright 1998 W.B. Saunders Company.)

Hepatobiliary dysfunction associated with the use of total parenteral nutrition is a commonly recognized phenomenon occurring in up to 90% of patients on long-term therapy. Reasons for these abnormalities, both supported by research as well as theoretical possibilities are explored. Practical guidelines considered useful in documenting, preventing and treating serious hepatic consequences of total parenteral nutrition are discussed. The role of combined liver and small bowel transplantation as treatment for select patients is also reviewed.

Background: In a randomized, controlled study we investigated the clinical efficacy of the microemulsion formulation of cyclosporine (Neoral) in comparison with Sandimmune (SIM) in the treatment of patients who underwent primary orthotopic liver transplantation (OLT)., Methods: In total, 33 patients were randomized in a double-blind fashion before undergoing primary OLT to receive either Neoral or SIM. All 33 patients initially received intravenous cyclosporine, but as soon as it was tolerated, the oral study drug was initiated (median time, 3.6 days) and 17 patients received Neoral and 16 SIM (for both drugs, 10 mg/kg/day). Both groups were comparable with regard to age, sex, etiology of chronic liver disease, and hepatic biochemical profile. Episodes of rejection were diagnosed histologically and characterized as mild, moderate, or severe using criteria from the National Institute of Diabetes and Digestive and Kidney Diseases., Results: Patients were followed for 1 year. Four patients in each group were discontinued prematurely. The reason for discontinuation of cyclosporine was drug-related complications in two of the NEO patients and in three of the SIM group; the other three were non-drug-related. Rejection episodes occurred in 9 of 17 patients (52.90%) in the Neoral group and in 9 of 16 patients (56.3%) in the SIM group. The total number of rejection episodes in each group was 14. However, in evaluating the severity of rejection histologically, nine episodes of rejection were characterized as moderate/ severe in the SIM group compared with only three in the Neoral group (P=0.027). Five of the nine moderate/severe rejection episodes in the SIM group occurred within the first 2 weeks after transplant. In contrast, moderate/severe rejection did not occur in the Neoral group in this early period. Two patients in the SIM group and no patients in the Neoral group required treatment with OKT3 for steroid-resistant rejection. There were no differences in mean doses or trough levels when comparing the two study groups. The incidence of adverse effects was similar in the two groups., Conclusions: Neoral is a safe and efficacious drug in the treatment of primary OLT patients. Given comparable doses of cyclosporine in each group over 1 year, there was no significant difference in the total number of rejection episodes between study groups. However, patients treated with Neoral had a lower incidence of moderate/severe histologic rejection and were free of steroid-resistant rejection when compared with SIM-treated patients.

Background: A study was performed by 17 different U.S. liver transplantation centers to determine the safety and efficacy of conversion from cyclosporine to tacrolimus for chronic allograft rejection., Methods: Ninety-one patients were converted to tacrolimus a mean of 319 days after liver transplantation. The indication for conversion was ongoing chronic rejection confirmed by biochemical and histologic criteria. Patients were followed for a mean of 251 days until the end of the study., Results: Sixty-four patients (70.3%) were alive with their initial hepatic allograft at the conclusion of the study period and were defined as the responder group. Twenty-seven patients (29.7%) failed to respond to treatment, and 20 of them required a second liver graft. The actuarial graft survival for the total patient group was 69.9% and 48.5% at 1 and 2 years, respectively. The actuarial patient survival at 1 and 2 years was 84.4% and 81.2%, respectively. Two significant positive prognostic factors were identified. Patients with a total bilirubin of < or = 10 mg/dl at the time of conversion had a significantly better graft and patient survival than patients converted with a total bilirubin > 10 mg/dl (P=0.00002 and P=0.00125, respectively). The time between liver transplantation and conversion also affected graft and patient survival. Patients converted to tacrolimus < or = 90 days after transplantation had a 1-year actuarial graft and patient survival of 51.9% and 65.9%, respectively, compared with 73.2% and 87.7% for those converted > 90 days after transplantation. The mean total bilirubin level for the responder group was 7.1 mg/dl at the time of conversion and decreased significantly to a mean of 3.4 mg/dl at the end of the study (P=0.0018). Thirteen patients (14.3%) died during the study. Sepsis was the major contributing cause of death in most of these patients., Conclusions: Our results suggest that conversion to tacrolimus for chronic rejection after orthotopic liver transplantation represents an effective therapeutic option. Conversion to tacrolimus before development of elevated total bilirubin levels showed a significant impact on long-term outcome.

Background: The optimal prophylactic regimen to prevent cytomegalovirus (CMV) infection and disease in orthotopic liver-transplant patients remains to be established. We tested whether a combination of intravenous ganciclovir (GCV) followed by high dosages of oral acyclovir (ACV) for 4 months provided a higher degree of protection from CMV than oral ACV alone., Methods: One hundred sixty-seven liver-transplant recipients were randomized to receive 120 days of antiviral treatment starting at the time of transplantation consisting of either ACV 800 mg orally four times daily (n=84) or 14 days of GCV 5 mg/kg intravenously every 12 hr followed by oral ACV 800 mg four times daily (n=83). Prospective laboratory and clinical surveillance was performed to determine primary endpoints (onset of CMV infection and CMV disease) and secondary endpoints (rates of fungal and bacterial infection, allograft rejection, and survival after transplantation). One-year event rates are presented as cumulative percentages., Results: During the first year after transplantation, CMV infection developed in 57% of patients treated with ACV and in 37% of patients treated with GCV + ACV (P=0.001). CMV disease developed in 23% of patients treated with ACV and in 11% of patients treated with GCV + ACV (P=0.03). In seronegative recipients of allografts from CMV-seropositive donors (D+/R-), CMV disease developed in 58% of patients treated with ACV and in 25% of patients treated with GCV + ACV (P=0.04). In the D+/R- group, 54% of patients treated with ACV and 17% of patients treated with GCV + ACV developed infection with Candida albicans (P=0.05)., Conclusions: Prophylaxis of CMV infection in liver-transplant patients with 14 days of intravenous GCV followed by high-dosage oral ACV is more effective than high-dosage oral ACV alone at reducing CMV infection and disease, even for patients in the D+/R- CMV serological group.