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Objective: To determine the level of association between minimal listing criteria (MLC) recognition and outcomes associated with waiting list registration for liver transplantation (LT)., Patients and Methods: A total of 147 patients and 201 patients were identified as first-time referrals for LT evaluation between January 1, 1997, and November 30, 1997 (cohort A), and December 1,1997, and December 31, 1998 (cohort B), respectively. Relevant demographic and clinical information was abstracted from medical records. Minimal listing criteria were defined as a Child-Turcotte-Pugh (CTP) score of 7 or higher., Results: Patient age, sex, hepatic disease etiology, and mean CTP scores were similar between cohorts A and B. However, the proportion of registered patients in cohort B with CTP scores of 7 or higher increased significantly after formal MLC recognition (96% vs 82% for cohort A; P=.001). In cohort A, waiting list registration was based on patient age, male sex, nonalcohol-related hepatic disease, and a CTP score of 7 or higher in the absence of formal MLC. The rate of first-time patient referral was also increased in cohort B vs cohort A after formal MLC recognition (80% vs 69%, respectively; P=.002) despite similar clinical characteristics. Although the number of patients with a CTP score of 10 or higher was greater in cohort B vs cohort A, the proportion of patients with advanced end-stage liver disease was similar (29% vs 26%, respectively; P=.72)., Conclusion: The explicit recognition of MLC was strongly associated with improvements in appropriate waiting list registration for LT.

Advances in liver transplantation continue to evolve but are hampered by continued increasing shortages in donor organs. This has resulted in a high incidence of patients dying while on the United Network for Organ Sharing waiting list. Indeed, we continue to assess ways of expanding the donor pool by using marginal donors, living donor liver transplantation, split liver transplantation, domino transplantation, and hepatic support systems to prolong survival long enough for the patient to undergo liver transplantation. Changes in the liver allocation policy to reduce the number of people dying while waiting for an organ are discussed. Implementation of the model for end-stage liver disease allocation system should help alleviate the problem of increasing deaths of patients while on the waiting list. Recurrent disease, particularly recurrent hepatitis C, continues to be a major problem, and effective therapy is needed to prevent both progression of hepatitis C and recurrence in the graft and avoid retransplantation. The use of pegylated interferon in combination with ribavirin holds promise for improving the success in overcoming recurrent hepatitis C. Finally, advances in immunosuppression have reduced the incidence of acute cellular rejection and chronic rejection. However, these therapies have been fraught with metabolic complications that are now affecting quality of life and long-term survival. Tailoring immunosuppressive regimens to the individual patient is discussed.

Objective: To describe a natural history model for primary sclerosing cholangitis (PSC) that is based on routine clinical findings and test results and eliminates the need for liver biopsy., Patients and Methods: Using the Cox proportional hazards analysis, we created a survival model based on 405 patients with PSC from 5 clinical centers. Independent validation of the model was undertaken by applying it to 124 patients who were not included in the model creation., Results: Based on the multivariate analysis of 405 patients, a risk score was defined by the following formula: R = 0.03 (age [y]) + 0.54 loge (bilirubin [mg/dL]) + 0.54 loge (aspartate aminotransferase [U/L]) + 1.24 (variceal bleeding [0/1]) - 0.84 (albumin [g/dL]). The risk score was used to obtain survival estimates up to 4 years of follow-up. Application of this model to an independent group of 124 patients showed good correlation between estimated and actual survival., Conclusions: A new model to estimate patient survival in PSC includes more reproducible variables (age, bilirubin, albumin, aspartate aminotransferase, and history of variceal bleeding), has accuracy comparable to previous models, and obviates the need for a liver biopsy.

In patients with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), risk score models that reflect disease severity have been developed and can serve as an objective measurement to assess and evaluate the effect of the severity of liver disease on the outcome of liver transplantation. Thus, using the established Mayo risk scores for PBC and PSC, one not only can estimate survival for the individual patient but can measure disease activity as well. Indeed, several studies have suggested that the optimal timing of liver transplantation with use of the Mayo PBC model may be an important tool to improve survival, decrease morbidity, and decrease overall related costs. Likewise, studies in patients with PSC have yielded similar results. This review explores how prognostic mathematical survival models for PBC and PSC might be applied to individual patients in need of liver transplantation. The following question is addressed: How can the timing of liver transplantation be optimized to increase survival, decrease postoperative morbidity, and ultimately, decrease the overall resource utilization involved in this procedure?

In the hepatopulmonary syndrome (HPS), a pulmonary vascular complication of liver disease, severe hypoxemia due to pulmonary vascular dilatation can be extremely debilitating. Determining whether patients with advanced liver disease and HPS should be considered for liver transplantation is difficult. We describe three patients with progressive and severe hypoxemia who underwent successful liver transplantation and had resolution of their arterial hypoxemia. In these patients, the progressive pulmonary deterioration accelerated the need and was considered an indication for liver transplantation rather than being considered an absolute or relative contraindication. In addition, we review the literature on 81 pediatric and adult patients with HPS who underwent liver transplantation and specifically highlight mortality, morbidity, syndrome resolution, and prognostic factors. Posttransplantation mortality (16%) was associated with the severity of hypoxemia (mean arterial oxygen tension [PaO2] in 68 survivors was 54.2 +/- 13.2 mm Hg and in 13 nonsurvivors was 44.7 +/- 7.7 mm Hg; P<0.03). Patients with a pretransplantation PaO2 of 50 mm Hg or lower had significantly more frequent mortality (30%) in comparison with those with a PaO2 greater than 50 mm Hg (4%; P<0.02). Pulmonary recommendations that address the severity of hypoxemia and candidacy for liver transplantation are discussed.

Objective: To compare the operative risks, operative complications, and late outcome of two homogeneous groups of patients with chronic ulcerative colitis (CUC) and primary sclerosing cholangitis (PSC) who underwent either Brooke ileostomy or ileal pouch-anal anastomosis (IPAA)., Material and Methods: Between 1970 and 1990, 72 patients with CUC and PSC underwent proctocolectomy with either Brooke ileostomy (group I; N = 32) or IPAA (group II; N = 40). Postoperative data included operative mortality, need for blood transfusion, general postoperative complications, liver-related complications, and proctocolectomy-related complications., Results: Eight group I patients and nine group II patients had a total of 12 and 11 general complications, respectively. Liver-related complications were diagnosed in 16% and 10% of group I and group II patients, respectively. Proctocolectomy-specific complications occurred in 34% of group I and 20% of group II patients. The overall need for blood transfusion was 94% in group I and 47% in group II (P < 0.001). The cumulative probability of proctocolectomy-related complications at 5 years was 23% for group I and 64% for group II patients (P < 0.002). The difference, however, was primarily due to the high frequency of pouchitis after IPAA, estimated at 57% at 4 years. The cumulative 5-year risk of liver-related complications was 37% and 28% for group I and group II, respectively. Peristomal varices and bleeding occurred in eight group I patients but in none of group II., Conclusion: Because IPAA avoids bleeding problems, it is the surgical treatment of choice in patients with PSC and CUC.

Objective: To characterize the pulmonary hemodynamics and identify predictors of pulmonary hypertension in a group of patients before liver transplantation and to determine whether pulmonary hypertension in these patients is related to survival., Material and Methods: In 362 patients before their first liver transplantation (between 1985 and 1993), the clinical history, laboratory data, and results of pulmonary function tests were recorded. Pulmonary artery (PA) catheterization was performed after induction of anesthesia at the time of transplantation. Monthly follow-up was maintained., Results: A hyperdynamic circulation was often present -- an increased mean cardiac output (7.6 L/min), increased mean PA pressure (20.9 mm Hg), correlation of mean PA pressure with cardiac output (r = 0.25; P<0.001), and decreased mean pulmonary vascular resistance (60 dynes times s/cm5). Mean PA pressures were more than 25 mm Hg in 72 patients (20%). Pulmonary hypertension (defined as mean PA pressure of more than 25 mm Hg and pulmonary vascular resistance in excess of 120 dynes times s/cm5) occurred in 15 patients (4%). Pulmonary function tests revealed obstruction in 7%, restriction in 18%, and low diffusing capacity in 46%. By univariate analysis, lower forced expiratory volume in 1 second, forced vital capacity, and total lung capacity were the only preoperative factors associated with pulmonary hypertension (P<0.05). Survival was significantly lower in patients with acute fulminant hepatitis (P<0.001), the group with the highest mean PA pressure, than in those with other diagnoses. Increased PA pressures or mild to moderate pulmonary hypertension was not found to be associated with a worse survival by univariate or multivariate analysis., Conclusion: Increased PA pressure is common in liver transplant patients (20%). "True" pulmonary hypertension occurred in only 4% of our patients and was not associated with an adverse outcome.

Objective: To analyze possible causative mechanisms for intracranial hemorrhage after orthotopic liver transplantation., Design: We conducted a retrospective survey of medical records and a case-control comparison in patients who had undergone liver transplantation during the period 1986 through 1992., Material and Methods: In a group of 8 patients with intracranial hemorrhage after orthotopic liver transplantation and a control series of 207 patients who had undergone liver transplantation but did not have intracranial hemorrhage, we summarized pertinent clinical and laboratory data and statistically analyzed potential risk factors for hemorrhage., Results: In the eight study patients, intracerebral hematomas were located in the parietal or frontal lobe in six, the cerebellum in one, and the putamen in one. Autopsy demonstrated a Candida-associated mycotic aneurysm in one of the eight patients, and one had disseminated aspergillosis. No statistically significant differences in thrombocytopenia, hypertension, extracranial bleeding sites, or cyclosporine-related neurotoxicity were found when these patients were compared with the control series. Bacteremia or fungemia was found in five of the eight patients with intracerebral hemorrhages (62%) but in only 11% of the control group (P = 0.03; Fisher's exact test)., Conclusion: Overwhelming infections, thrombocytopenia, or both may have a role in intracerebral hemorrhage after liver transplantation.

Objective: To describe a series of consecutive patients with fulminant hepatic failure (FHF) and to present a new classification system for brain edema, an important cause of mortality in such patients., Design: We reviewed 22 computed tomographic (CT) scans of the brain in 12 patients with FHF and classified the severity of cerebral edema by using predefined criteria., Results: No cerebral edema was detected on CT scans in four patients with stage 1 or 2 hepatic encephalopathy at the time of admission, but it was noted in seven of eight patients with stage 3 or 4 hepatic encephalopathy. The severity of brain edema on CT scans was significantly correlated (P < 0.001) with the stage of hepatic encephalopathy. Three of the four patients who had stage 1 or 2 hepatic encephalopathy at the time of initial assessment ultimately had a good outcome. Of seven patients with stage 3 encephalopathy, two had rapid deterioration to brain death, three died of nonneurologic causes, and two had a good outcome after liver transplantation. One patient with stage 4 hepatic encephalopathy died, and autopsy showed cerebral edema., Conclusion: Stage 3 or 4 hepatic encephalopathy is associated with cerebral edema that can be detected on CT scans. The clinical and radiologic signs of cerebral edema in patients who have progression to stage 3 hepatic encephalopathy can be reversed with conventional treatment of increased intracranial pressure. Whether early recognition and treatment of cerebral edema result in increased survival of patients with FHF remains to be determined.

Objective: To describe the features and mechanisms of posttransplantation hypertension and suggest appropriate management of the disorder., Design: We review our own experience and reports from the literature on hypertension in cyclosporine A (CSA)-treated transplant recipients., Results: Soon after immunosuppression with CSA and corticosteroids, hypertension develops in most patients who undergo transplantation. The blood pressure increases, which are usually moderate, occur universally because of increased peripheral vascular resistance. Disturbances in circadian patterns of blood pressure lead to loss of the normal nocturnal decline, a feature that magnifies hypertensive target effects. Changes in blood pressure sometimes are severe and associated with rapidly developing target injury, including intracranial hemorrhage, left ventricular hypertrophy, and microangiopathic hemolysis. The complex mechanisms that underlie this disorder include alterations in vascular reactivity that cause widespread vasoconstriction. Vascular effects in the kidney lead to reduced glomerular filtration and impaired sodium excretion. Many of these changes affect local regulation of vascular tone, including stimulation of endothelin and suppression of vasodilating prostaglandins. Effective therapy includes use of vasodilating agents, often calcium channel blocking drugs. Caution must be exercised to avoid interfering with the disposition of CSA or aggravating adverse effects relative to kidney and electrolyte homeostasis., Conclusion: Recognition and treatment of CSA-induced hypertension and vascular injury are important elements in managing the transplant recipient.

Objective: To describe primary sclerosing cholangitis (PSC) and its associated complications, as well as medical and surgical treatment., Design: A review of PSC and its associated etiopathologic factors is presented; numerous studies of agents that are used to treat patients with PSC are discussed., Results: PSC, a slowly progressive disease that often involves autoimmune damage to the biliary tree, is frequently associated with inflammatory bowel disease, usually chronic ulcerative colitis. Long-term follow-up of patients with PSC has revealed a high incidence of colon cancer and bile duct cancer, both of which are most likely related to the chronic inflammation involving these two organs. Although PSC is an unusual disease, it is now diagnosed with approximately the same frequency as is primary biliary cirrhosis. The histopathologic evolution of PSC results in irreversible damage to bile ducts, which ultimately leads to cholestasis, cirrhosis, liver failure, and premature death from liver failure unless liver transplantation is performed. Therefore, the best chance of achieving success is to treat patients with early-stage disease rather than those with irreversible end-stage cirrhotic disease. Although several medical therapies for PSC have been evaluated, only D-penicillamine, cyclosporine, methotrexate, and, most recently, ursodeoxycholic acid have been studied in controlled clinical trials. Furthermore, several surgical therapies for PSC and its associated complications have been assessed., Conclusion: Currently, no therapy achieves a complete clinical, biochemical, or histologic remission in this disease. Until the etiopathogenesis of PSC is further defined, effective therapy is unlikely to be found. Thus, liver transplantation will continue to be an important therapeutic intervention for the management of patients with end-stage PSC.

Objective: To report our experience with orthotopic liver transplantation (OLT) for highly selected patients with early-stage hepatocellular carcinoma (HCC)., Design: We retrospectively analyzed the demographic, clinical, pathologic, and survival data on 21 patients with HCC who underwent OLT at the Mayo Clinic between 1985 and 1993., Material and Methods: The 21 patients were categorized into three groups: (1) those with incidental HCC (no evidence of HCC preoperatively), (2) those with a unicentric hepatic lesion without vascular invasion, and (3) those with an increased serum alpha-fetoprotein (AFP) concentration but no detectable mass lesion in the liver., Results: For the seven patients with incidental HCC, the 2-year disease-free survival was 68.5%. For the eight patients with a mass lesion, the 2-year disease-free survival was only 50%. Operative staging revealed more advanced stage disease than had been found on preoperative assessment in five of these eight patients. For the six patients with an increased serum AFP value but no mass lesion, the 2-year disease-free survival was 80%. Tumor recurrence was the major cause of all deaths in this series., Conclusion: Disease-free survival for patients with radiographic early-stage HCC was suboptimal because of understaging of the disease preoperatively. In contrast, our initial experience with OLT for patients with an increased serum AFP value in the absence of a mass lesion in the liver was favorable.

Objective: To characterize the caloric and protein requirements of patients with end-stage liver disease before and for 28 days after liver transplantation., Design: We prospectively assessed 16 adult patients who were scheduled to undergo liver transplantation between December 1989 and September 1990., Material and Methods: Nitrogen balance, 24-hour urinary creatinine, 3-methylhistidine, and resting energy expenditure were determined before transplantation and on days 1, 3, 5, 14, and 28 after transplantation. The investigators were unaware of the results of these measurements, and patients were fed in accordance with a previously established clinical protocol., Results: Resting energy expenditure did not increase from preoperative values; however, urinary nitrogen and 3-methylhistidine increased significantly after liver transplantation, an indication of protein catabolism from a myofibrillar source. A negative nitrogen balance persisted for 28 days post-operatively., Conclusion: We recommend that caloric intake be determined by using the formulation provided by the Harris-Benedict equation at ideal body weight plus 20%. We also recommend that intake of protein be adjusted on the basis of preoperative nutritional assessment, perioperative hepatic and renal function, and results of tests used to measure the adequacy of administered protein. Parenterally or enterally administered protein of more than 1.2 g/kg daily should be well tolerated in most patients who have undergone liver transplantation.

Objective: We conducted a treatment trial to determine the relative toxicity of FK-506 and cyclosporine A (CSA) in liver transplant recipients., Design: Between October 1990 and October 1991, 37 patients were enrolled in an open-labeled, randomized study of two immunosuppressive regimens after liver transplantation., Material and Methods: Of the 23 men and 14 women, 20 received FK-506 plus prednisone, and 17 received CSA plus prednisone and azathioprine. Renal function was assessed before and after transplantation (day 1, month 1, month 4, and month 12) by measurements of serum creatinine (SCr) and glomerular filtration rate (GFR) as determined by urinary iothalamate or creatinine clearance (or both). FK-506 trough plasma levels (enzyme immunoassay) were to be maintained between 0.2 and 5.0 ng/mL, and CSA trough blood levels (whole blood high-performance liquid chromatography) were to be maintained between 250 and 400 ng/mL. Severe nephrotoxicity was defined as sudden decreases in urine output to less than 10 mL/h or rapid increases in SCr (more than 0.5 mg/dL daily) that necessitated withdrawal of study medication for more than 48 hours. Mean patient age and values for SCr and GFR were comparable between the two groups at entry., Results: Both study groups demonstrated a similar deterioration in renal function during a 12-month follow-up, although patients who received FK-506 had a significantly (P < 0.05) lower GFR when measured at 12 months than did patients treated with CSA (45 +/- 4 versus 64 +/- 6 mL/min per body surface area). Mild nephrotoxicity that responded to decreased drug doses was noted in 9 CSA-treated patients (53%) and 10 FK-506-treated patients (50%). Severe nephrotoxicity that necessitated drug withdrawal occurred in only four patients, all of whom were in the FK-506 group. These severe nephrotoxic reactions to FK-506 occurred early after transplantation, often during intravenous administration of the drug, and were not associated with poor liver allograft function or drug levels outside the therapeutic range., Conclusion: Both FK-506 and CSA are significantly nephrotoxic in liver transplant recipients. In this trial, however, we observed an early development of severe nephrotoxic reactions only in some patients who received FK-506.

We analyzed the immunophenotypes of hepatic cellular infiltrates by quantitative immunohistochemical methods in biopsy specimens from 20 patients with primary biliary cirrhosis (PBC), 19 with primary sclerosing cholangitis, and 11 with autoimmune chronic active hepatitis. Specifically, we sought to identify activated T cells, interferon-gamma-producing cells, and natural killer cells. The portal cellular infiltrate in PBC contained a preponderance of CD4 cells in comparison with CD8 cells, with a CD4/CD8 ratio of 2.45:1. The cellular infiltrate in areas of piecemeal necrosis contained mostly CD8 cells. Infiltrating CD8 cells in PBC had the surface phenotype of cytotoxic (CD8-positive, CD11b-negative) cells. Approximately 4% of T cells expressed interleukin 2 receptors. Interferon-gamma-staining cells were rarely identified (in less than 2%). Cells that expressed the natural killer cell markers CD16, CD56, or CD57 were infrequent, constituting approximately 5% of the cellular infiltrate. The composition of the infiltrates was similar in patients with PBC and chronic active hepatitis. Natural killer cells were twice as common in patients with primary sclerosing cholangitis (P < 0.05) as in those with PBC. The inflammatory infiltrates in areas of piecemeal necrosis were similar in the three diseases and differed from those found within the portal area, in that CD8 cells were preponderant. In all three liver diseases, almost 90% of bile ducts expressed class II HLA antigens. These findings support the hypothesis that cytotoxic T cells of either the CD4 or CD8 immunophenotype but not natural killer cells may be involved in the pathogenesis of PBC and chronic active hepatitis.(ABSTRACT TRUNCATED AT 250 WORDS)

Primary sclerosing cholangitis (PSC) predisposes to the development of cholangiocarcinoma, a usually fatal complication that is difficult to diagnose. Serum concentrations of CA 19-9, a tumor-associated antigen, are frequently increased in patients with only cholangiocarcinoma. The aim of this study was to assess the value of an increased serum CA 19-9 level for the diagnosis of cholangiocarcinoma in patients with preexisting PSC. We analyzed serum samples from 9 patients with PSC and superimposed cholangiocarcinoma and from 28 patients with only PSC. Serum concentrations of CA 19-9 were measured in a blinded manner with use of an immunoradiometric assay. The serum CA 19-9 concentrations were increased in 8 of 9 patients (89%) with PSC and cholangiocarcinoma (mean +/- SE, 391 +/- 86 U/ml; range, 4 to 677), whereas they were increased in only 4 of 28 patients (14%) with only PSC (mean +/- SE, 61 +/- 16 U/ml; range, 2 to 370). The sensitivity of a CA 19-9 value greater than 100 U/ml for cholangiocarcinoma in PSC was 89%, and the specificity was 86%. The measurement of serum concentrations of CA 19-9 is a promising test for detecting cholangiocarcinoma in patients with PSC.

Hepatic allograft rejection remains a major cause of morbidity related to the need for increased immunosuppression and continues to be a principal cause of late failure of the graft. Hepatic allograft rejection is defined on the basis of morphologic findings; cellular rejection is defined as portal or periportal hepatitis with nonsuppurative cholangitis or endotheliitis (or both), and ductopenic rejection is defined as loss of interlobular and septal bile ducts, typically in at least 50% of the portal tracts. The overall incidence of episodes of cellular rejection, which usually occur within the first 2 weeks after liver transplantation, varies from 50 to 100%. Ductopenic rejection occurs in approximately 8% of patients who undergo initial liver transplantation and is usually diagnosed between 6 weeks and 6 months after transplantation. Induction and maintenance immunosuppression with triple-drug (cyclosporine, prednisone, and azathioprine) therapy and other combinations that include antilymphocyte preparations, however, has decreased the incidence of both cellular and ductopenic rejection. In patients experiencing episodes of cellular rejection, high-dose intravenously administered corticosteroid therapy yields the best response and is associated with a lower incidence of ductopenic rejection than is low-dose and orally administered corticosteroid therapy. The correlation between degree of biochemical liver dysfunction and presence of histologic rejection is minimal early after transplantation. Histologic severity of rejection, however, suggests which patients will require more immunosuppression and which patients may need antilymphocyte therapy for controlling the rejection episode. With the availability of new immunosuppressive agents, distinguishing patients at high risk for rejection is important. The goals for use of new immunosuppressive agents and regimens are to improve graft and patient survival, to decrease the incidence of cellular and ductopenic rejection, and to minimize side effects and complications.

Duplex ultrasonography plays an important role in the preoperative and postoperative assessment of liver transplant patients. Before surgical intervention, the principal use of sonography is to assess the patency of the extrahepatic portal vein because a narrowed or thrombosed portal vein may preclude transplantation. Postoperatively, several potential complications can lead to allograft dysfunction (rejection, infection, vascular thromboses, and biliary tract complications). Because these complications often manifest with variable and nonspecific symptoms, diagnosing them can be difficult. Sonography is a valuable noninvasive means of evaluating postoperative complications in liver transplant patients. When vascular complications are suspected, duplex sonography is the optimal screening procedure for assessment of the vascular anastomoses. Focal parenchymal abnormalities (hematomas, infarcts, and bilomas) and localized collections of abdominal fluid are readily detected by ultrasonography and can be safely aspirated and, when infected, percutaneously drained under sonographic guidance. Sonography is less useful in the detection of biliary tract complications early after transplantation.

Anesthesia support for patients undergoing orthotopic liver transplantation can be complicated because of multiple medical problems in such patients and rapid hemodynamic, metabolic, and coagulation changes intraoperatively. Preoperative assessment should include careful review of the cardiovascular, respiratory, and hematologic systems. Use of isoflurane as the main anesthetic agent will minimize toxicity to the liver. During liver transplantation, hemodynamic monitoring and immediate laboratory studies should be available. In our experience during the first 100 liver transplantations performed at our institution, use of a rapid infusion pump and venovenous bypass has helped normalize hemodynamic and renal function.

Nutritional assessment factors (including dietary history, anthropometric and biochemical measurements, and evaluation of immunocompetence) were retrospectively reviewed in 74 patients undergoing an initial liver transplantation procedure. The patients were subdivided into four categories on the basis of type of liver disease: chronic active hepatitis (N = 24), primary sclerosing cholangitis (N = 22), primary biliary cirrhosis (N = 20), and acute or subacute hepatitis (N = 8). Our nutritional assessment data indicated that malnutrition was present preoperatively in all liver transplantation groups but that each group had distinct characteristics. The group with primary biliary cirrhosis seemed to have the best hepatic synthetic function despite extreme wasting of muscle and fat. On the basis of all criteria, the group with acute hepatitis was the most malnourished of the various disease groups. Aggressive nutritional support, which includes adequate intake of nutrients and supplementation of vitamins and trace minerals, should be encouraged for all potential liver transplant patients.

We retrospectively reviewed the long-term results in 46 patients who survived at least 1 year after liver transplantation. Only one death has occurred, and one patient has required retransplantation. Biochemical liver function tests showed median values in the normal range, except for mild elevation of serum gamma-glutamyltransferase. In patients with primary biliary cirrhosis, these test results were completely normal. A liver biopsy 1 year after transplantation disclosed normal histologic findings in 31 patients (67%). The other patients had either transient (acute rejection) or stable (chronic rejection) abnormalities, except for two patients with progressive graft dysfunction attributable to chronic rejection. A clinically significant vascular anastomotic abnormality was noted in one patient who had hepatic artery thrombosis. Late bile duct complications occurred in 15% of patients, all of whom had a satisfactory outcome after surgical or radiologic intervention. Cyclosporine-related nephrotoxicity and hypertension each occurred in 67% of patients; however, conversion to a low-dose cyclosporine-azathioprine regimen yielded stabilization of renal function after the first postoperative year, and hypertension has been easily controlled medically. Diabetes necessitating insulin treatment developed in three patients. The body weight of the study patients had increased by a median of 6.5 kg at 1 year but stabilized thereafter. Subjective well-being and satisfaction with life were reported by 91% of the patients. Of the 46 patients, 26 were employed, 16 were homemakers, and only 4 did not work, 2 because of transplant-related medical problems. Thus, we conclude that liver transplantation rehabilitates patients with end-stage liver disease and enhances their quality of life.

Whipple's disease is a chronic systemic illness, the optimal treatment of which remains poorly defined. In our analysis of a 30-year, 29-patient experience with Whipple's disease at the Mayo Clinic, the frequent initial manifestations of diarrhea, weight loss, arthritis, and lymphadenopathy correlated with findings reported previously by other investigators. Antibiotic therapy yielded rapid symptomatic and biochemical improvement, and histologic changes in the small bowel occurred subsequently. Despite antimicrobial therapy, relapses in patients with Whipple's disease are common, and the central nervous system is considered the most serious site of involvement for recurrence. Administration of an antibiotic agent that is able to cross the blood-brain barrier may be more important in preventing relapse than prolonged duration of initial antimicrobial therapy.

Successful implementation of a liver transplantation program is dependent on extensive blood bank support. Careful planning, organization, and coordination of the blood bank and other clinical services are necessary. In our first 100 orthotopic liver transplantations, our median intraoperative erythrocyte use was 12.6 units, and 30% of the erythrocytes were provided by intraoperative cell salvage. Thus, the need for homologous blood and the number of donors to whom recipients were exposed were reduced. Use of intraoperative cell salvage and expansion of our erythrocyte inventory through the use of AS-1 preservative helped us meet the demands of the liver transplant program without compromising the availability of blood products for all other surgical and medical patients.

We retrospectively reviewed the results of preoperative hematology-coagulation studies in 66 patients who underwent orthotopic liver transplantation-24 with the primary diagnosis of chronic active hepatitis (CAH), 22 with primary sclerosing cholangitis (PSC), and 20 with primary biliary cirrhosis (PBC). The mean prothrombin time was above normal in all three diagnostic groups, patients with CAH having the highest values. The mean activated partial thromboplastin time was normal in patients with PSC or PBC but elevated in those with CAH. Fibrinogen levels were above normal in patients with PBC but decreased in 1 patient (5%) with PSC and 10 (42%) with CAH. Mean platelet counts were below normal in 68% and 55% of patients with PSC and PBC, respectively, but in 96% of those with CAH. The mean Ivy bleeding time was normal in patients with PSC or PBC but prolonged in those with CAH. Patients with PSC or PBC had normal mean activity levels of factors II, V, VII, IX, and X, whereas those with CAH had below normal mean values for factors II and VII. The antithrombin III activity level was normal in patients with PSC or PBC but reduced in those with CAH. Thus, patients with CAH have a greater derangement in results of clotting studies in comparison with those who have PSC or PBC, but the use of blood did not differ among the three diagnostic groups.

A detailed coagulation and thromboelastographic study was done on the first 50 liver transplantation procedures performed at the Mayo Clinic between March 1985 and June 1986. Most of the patients suffered from primary sclerosing cholangitis, primary biliary cirrhosis, or chronic active hepatitis. Seven patients required a second liver transplantation, and six patients died, none intraoperatively. Most of the patients had distorted hemostatic mechanisms preoperatively, as would be expected because the liver generates most of the clotting factors. The outstanding exception was factor VIII, which was usually in the high-normal range or even more elevated. Substantial deterioration of coagulation factors occurred regularly during reperfusion of the donor liver. In some instances, this trend was corrected within 1 hour, but platelet counts continued to decrease, and some coagulation factors rebounded only partially. Because thromboelastographic tracings are quickly available to the liver transplant team and because they tend to forewarn of impending hemostatic problems, we believe that thromboelastography is a reasonably effective procedure for monitoring coagulation during liver transplantation.

Of 83 patients who underwent 100 orthotopic liver transplantations, 53 had a single transplant procedure and at least 6 months of follow-up. In this main study group of 53 patients, major infections developed in 28 (53%) (a mean of 1.8 major episodes per infected patient). Of 51 major infections, 27 were bacterial, 19 were viral, 3 were protozoan, and 2 were fungal. Of the 27 bacterial infections, 22 (81%) occurred in the first 2 months after transplantation. Of the 40 bacterial isolates in the 27 bacterial infections, gram-positive aerobic bacteria were isolated in 26 (65%), anaerobic bacteria in 8 (20%), and aerobic gram-negative bacteria in 6 (15%). Only 1 of 16 bacteremic episodes was due to a gram-negative aerobic bacterium. Cytomegalovirus (CMV) infection occurred in 30 of the 53 patients (57%) and was symptomatic and invasive in 18. CMV infection was diagnosed a mean of 26 days after transplantation. Infections due to Pneumocystis carinii occurred later (2 to 3 months after transplantation). Death from infection occurred in 4 of the 53 patients (8%). In the group of 16 patients with two or more liver transplantations, fungal infection occurred in 2 and CMV infection in 13. In all 16 patients who underwent more than one liver transplantation, a major infection developed. The observations made in the main study group were consistent with findings in 13 patients with one liver transplantation but less than 6 months of follow-up. Infection is a major complication after liver transplantation, generally occurring in the first 2 months. Our observations suggest that the use of selective bowel decontamination may be associated with a relatively lower incidence of gram-negative aerobic bacterial infections.

Endotheliitis (EN) is a feature of hepatic allograft rejection, characterized by the adherence of immunocytes to the endothelium of veins, often leading to endothelial damage, endophlebitis, and, sometimes, panphlebitis. We found EN at least once in 28 of 41 allografts (68%) that had survived 6 months or longer. In approximately half the affected cases, the condition recurred. The EN was mild in most instances; moderate or severe manifestations were found in only 13% of the cases. The histologic changes were present for about 1 week in approximately half the cases; a duration of more than 2 weeks was noted in 17%, and then EN usually persisted. After retransplantation, recurrence of EN was observed in all of nine cases. We were unable to establish specific clinicopathologic and laboratory correlations for EN. The immunocytes in EN consisted mainly of helper and suppressor/cytotoxic T cells as well as natural killer cells. Sometimes, the immunocytes assumed a blastlike appearance; in these instances, the condition was severe. Such blastlike changes may be specific for EN. The immunocytes were attached to the endothelium by pseudopodia, broad bases, or both; some also were interconnected by cytoplasmic bridges. Underlying endothelial cells often showed evidence of cytoplasmic damage. The pathogenesis of EN is not completely understood; the immunocytes probably attach themselves to antigenic epitopes. Their nature, however, has not been clearly identified; HLA-A, B, and C and HLA-DR were displayed in areas of EN, but the antigens also were found in vessels without EN.

In this study, we retrospectively analyzed the intraoperative hemodynamic, laboratory, and coagulation data on the first 83 patients who underwent an initial liver transplantation procedure at our institution. The major hemodynamic changes at the time of reperfusion of the donor liver were significant decreases in arterial blood pressure, systemic vascular resistance, and pulmonary artery temperature and significant increases in cardiac output and pulmonary capillary wedge pressure. The alterations in laboratory values reflected intraoperative therapeutic manipulations. Citrate toxicity is a concern, and the amount of calcium chloride administered reflected the volume of blood transfused. On reperfusion, the fibrinogen concentration decreased and both the prothrombin time and the activated partial thromboplastin time increased. This coagulopathy was also evident in the thromboelastographic values. Aggressive monitoring and prompt intervention are necessary to maintain hemodynamic and metabolic homeostasis in these patients.

Monoclonal antibodies were used to identify helper T cells (TH) and suppressor/cytotoxic T cells (TS/C) in liver allograft biopsy specimens obtained 7,21,90,180, and 365 days postoperatively and then annually or during episodes of graft dysfunction and after treatment of rejection episodes. Biopsy specimens were obtained from 70 hepatic allografts from patients treated with cyclosporine and corticosteroids. Rejection was diagnosed by the presence of appropriate laboratory and light microscopic findings and at least 16 weeks of follow-up to exclude other causes of graft dysfunction. Three immunohistologic patterns were noted: no or only a trace of T lymphocytes, predominantly TH infiltrate with or without a small amount of TS/C cells (portal TH), and a mixture of TH with an equal or greater number of TS/C infiltrate (portal mix). Of 68 biopsy specimens obtained during quiescent periods, only 3 had a portal tract T-lymphocyte infiltrate. Of 30 protocol biopsy specimens, 24 contained such an infiltrate a mean of 12.4 days before biochemical and routine histologic indications of rejection in the allograft. At the time of the rejection episode, 33 biopsy specimens were immunohistologically labeled; portal tract T-lymphocyte infiltrate was predominantly TH in 8 and a mixture of TH and TS/C in 25. All rejection episodes with a predominantly TH pattern responded to methylprednisolone. Of the 25 rejection episodes with a portal mix pattern, only 3 responded to methylprednisolone. Eighty-seven biopsy specimens were obtained more than 10 days after treatment of rejection.(ABSTRACT TRUNCATED AT 250 WORDS)

Between March 1985 and June 1987, the first 100 liver transplantations at the Mayo Clinic were performed in 83 patients (primarily adults). The most frequent diagnoses were chronic active hepatitis (in 24 patients), primary sclerosing cholangitis (in 22), and primary biliary cirrhosis (in 20). The median operating time was 406 minutes, and the median usage of erythrocytes was 13.2 units. A venovenous bypass was used in all patients older than 10 years of age. Hepatic artery thrombosis occurred in 10% of the 100 transplants. A choledochocholedochostomy was done in 58 patients and a choledochojejunostomy in 25 patients. Revision of the biliary anastomosis was necessary in 9 of the 83 patients (11%). Rejection, diagnosed by clinical and histologic criteria, occurred in 50 patients (60%) and was treated with a corticosteroid bolus, followed by OKT3 (monoclonal antibody) treatment if necessary. Selective bowel decontamination helped prevent infections; only 16 bacteremias occurred, 1 of which was caused by a gram-negative organism. Fungal infections were rare. Cytomegalovirus infection occurred in 47 patients (57%). Of the 83 patients, 16 required retransplantation, in 11 of whom graft rejection had occurred. One- and 2-year patient survival was 83% and 70%, respectively. Although problems still remain, liver transplantation is a reasonable option for patients with end-stage liver disease.

Liver transplantation is considered lifesaving for selected patients with end-stage primary biliary cirrhosis (PBC). A mathematical model to predict survival in the patient with PBC who has not undergone transplantation would be valuable for improving selection of patients for and timing of transplantation and for providing control information for assessment of the efficacy of transplantation. The Cox regression method and data from 312 Mayo Clinic patients with PBC were used to develop a model based on age, total serum bilirubin, serum albumin, prothrombin time, and severity of edema. When cross-validated on an independent set of 106 Mayo patients, the model accurately predicted their survival. It was similar to two other published survival models in terms of risk measurement but had the advantage of not necessitating liver biopsy. The model was used to assess the efficacy of liver transplantation by comparing the Kaplan-Meier survival of 32 Mayo patients after transplantation with the average model prediction of survival without transplantation. Beyond 3 months after transplantation, Kaplan-Meier survival probabilities were significantly greater than control survival predicted by the model (P less than 0.001). Examples of using the model for aiding in selection of patients for and timing of transplantation are provided.