Randomized, placebo-controlled, double-blind, multicenter trial of efficacy and safety of granulocyte colony-stimulating factor in liver transplant recipients.

BACKGROUND: Infection and rejection are two common complications after liver transplants. In a preliminary study, administration of granulocyte colony-stimulating factor (G-CSF) to liver transplant recipients was associated with a decrease in sepsis episodes, sepsis-related deaths, and rejection compared with a historical control group of patients. The purpose of this study was to evaluate further the efficacy of G-CSF in liver transplant patients in a randomized, placebo-controlled, double-blind, multicenter trial. METHODS: Adult patients with a United Network Organ Sharing classification of 1 or 2 were randomized to receive a placebo, 100 microg/day of G-CSF or 300 microg/day of G-CSF. The study drug was started preoperatively and then continued after the transplant for a maximum of 21 days. Patients were evaluated for microbiologically-documented infection, biopsy-proven rejection, number of treatments for rejection, length of stay in the intensive care unit and hospital, graft survival, death, and adverse events. RESULTS: During the first 30 days after the transplant, the median peak white blood cell count was 16.5x10(9)/L, 34.6x10(9)L, and 54.8x10(9)/L for the placebo, low-dose G-CSF, and high-dose G-CSF patients, respectively. The incidence of infection was 30% in G-CSF patients (34 of 114 patients) and 34% in placebo patients (20 of 58 patients). Except for more nosocomial pneumonias in the G-CSF patients (7 in 114 patients vs. 0 in 58 patients, P=0.056), the types of infections and causative organisms were also similar in both treatment groups. Although the number of treatments for clinically suspected or proven rejection was similar in the G-CSF and placebo patients, biopsy-proven rejection occurred more often in G-CSF patients (34 of 114 patients or 30%) than placebo patients (11 of 58 patients or 19%) (P=0.093). There were no cases of graft loss caused by rejection. G-CSF had no effect on length of stay in the intensive-care unit or hospital. There were 22 G-CSF patients (18%) and 10 placebo patients (15%) who died within 120 days after the transplant. No serious adverse events were attributed to G-CSF. CONCLUSION: Despite producing substantial increases in the white blood cell count after the transplant, G-CSF had no beneficial effects on infection, rejection, or survival in this study. Biopsy-proven rejection and nosocomial pneumonias were more common in patients treated with G-CSF compared with those taking the placebo. No serious adverse events were attributed to G-CSF.

Etiology and outcome for 295 patients with acute liver failure in the United States.

Little information is available on acute liver failure (ALF) in the United States. We gathered demographic data retrospectively for a 2-year period from July 1994 to June 1996 on all cases of ALF from 13 hospitals (12 liver transplant centers). Data on the patients included age, hepatic coma grade on admission, presumed cause, transplantation, and outcome. Among 295 patients, 74 (25%) survived spontaneously, 121 (41%) underwent transplantation, and 99 (34%) died without undergoing transplantation. Ninety-two of 121 patients (76%) survived 1 year after transplantation. Acetaminophen overdose was the most frequent cause (60 patients; 20%), followed by cryptogenic/non A non B non C (NANBNC; 15%), idiosyncratic drug reactions (12%), hepatitis B (10%), and hepatitis A (7%). Spontaneous survival rates were highest for patients with acetaminophen overdose (57%) and hepatitis A (40%) and lowest for those with Wilson's disease (no survivors of 18 patients). The transplantation rate was highest for Wilson's disease (17 of 18 patients; 94%) and lowest for autoimmune hepatitis (29%) and acetaminophen overdose (12%). Age did not differ between survivors and nonsurvivors, perhaps reflecting a selection bias for patients transferred to liver transplant centers. Coma grade on admission was not a significant determinant of outcome, but showed a trend toward affecting both survival and transplantation rate. These findings on retrospectively studied patients from the United States differ from those previously gathered in the United Kingdom and France, highlighting the need for further study of trends in each country.

Tamoxifen in liver disease: potential exacerbation of hepatic dysfunction.

Tamoxifen, a non-steroidal anti-estrogen, has been used successfully for a decade as post-operative adjuvant therapy for breast cancer. Tamoxifen is generally well tolerated with few side effects, especially at the typical dose of 10 mg twice daily. However, hepatic effects have been reported after tamoxifen administration and are usually found to be cholestatic in nature. Although previous reports concentrate on tamoxifen as a probable cause of drug-induced hepatotoxicity, very little attention has been focused on the use of tamoxifen in patients with pre-existing liver dysfunction and the possible need for dose adjustment. We present the case of a 48-year-old woman with an acute exacerbation of her pre-existing liver dysfunction and subsequent elevations of tamoxifen blood levels after approximately one year of tamoxifen therapy for adjuvant treatment of breast cancer. Tamoxifen dosing was adjusted based on serum levels.

Cholestatic hepatitis C in liver allografts.

Some liver allograft recipients with hepatitis C virus (HCV) infection develop hyperbilirubinemia, which might be the result of a cholestatic variant of hepatitis C. We evaluated all liver biopsy samples from 6 liver transplant recipients who had polymerase chain reaction-positive HCV infection and histologic evidence of hepatitis and jaundice and compared them with liver biopsy samples from a control group of transplant recipients with HCV hepatitis without jaundice. Patients with known ductopenic rejection, biliary obstruction, or co-infection with hepatitis A or B were excluded from the study. Measurement of viral titers and genomic typing were performed when possible. Six patients developed hepatitis and jaundice, with maximum bilirubin levels ranging from 5.8 to 47.6 mg/dL. In this group, 5 (83%) had moderate interface hepatitis (control group, 15%), 6 (100%) had confluent necrosis (control group, 12%), 5 (83%) had bridging fibrosis (control group, 18%), 4 (67%) had significant hepatocyte swelling (control group, 9%), 4 (67%) had prominent ductular proliferation (control group, 3%), and 6 (100%) had mild duct damage and inflammation (control group, 53%). All 6 of the patients with cholestasis had allograft failure. Of these, three allografts were available for review, which did not reveal occult obstruction, rejection, or duct loss. All patients in the control group have retained their allografts. In 4 patients with cholestasis, the median HCV RNA titer was 93.97 mEq/mL, with a mean of 54.19 mEq/mL (control mean = 5.2 mEq/mL). Five patients also underwent viral genomic typing: 2 with type 1a, 2 with type 1b, and 1 with mixed type 1a and 1b. Cholestasis in patients with posttransplantation hepatitis C may be caused by an aggressive HCV infection that exhibits histologic features of confluent necrosis, hepatocyte swelling, and/or ductular proliferation. Viral titers are often increased in such patients.

Enterococcal bacteremia after transjugular intrahepatic portosystemic shunts (TIPS).

The objective of this study was to analyze a series of patients with Enterococcus faecium infection following transjugular intrahepatic portosystemic shunts (TIPS) in order to define the risk factors, outcome, and role of treatment including hepatic transplantation. This study is a case series from a tertiary referral center for liver transplantation. The medical records of four patients referred to one teaching hospital in San Francisco between 1990 and 1995 for evaluation or management of Enterococcal infection following TIPS were reviewed. A review of the microbiology records of all 314 patients who underwent TIPS at that institution and a MEDLINE search were performed to assess whether any other cases existed. The effect of therapy on survival was assessed, in particular, the repeated use of TIPS and prolonged courses of antibiotics. All four patients had thrombosis of their TIPS at the time of diagnosis of enterococcal bacteremia. All were treated with prolonged courses of intravenous antibiotics. One patient had echocardiographic evidence of subacute bacterial endocarditis with chronic aortic insufficiency. In all cases, liver transplantation was contraindicated in the acute setting because of uncontrolled endovascular infection. Two of four patients survived; these were the only two patients who had had a successful repeat TIPS. Enterococcal bacteremia is a rare complication following TIPS but carries a high mortality. It usually occurs in the setting of technically difficult TIPS with shunt thrombosis. Management should be focused on long term antibiotics and attempts at reestablishment of portal decompression with another TIPS. Liver transplantation should not be considered until the infection is cleared. Prophylaxis for Enterococcus species should be considered in technically difficult or unsuccessful TIPS.

Severe hyperbilirubinemia after creation of transjugular intrahepatic portosystemic shunts: natural history and predictors of outcome.

BACKGROUND: Hyperbilirubinemia after creation of transjugular intrahepatic portosystemic shunts (TIPS) has been attributed to hemolysis and portal diversion, but the causes and natural history of this condition remain unknown. OBJECTIVE: To determine clinical outcomes and predictors of severe hyperbilirubinemia after TIPS creation. DESIGN: Retrospective analysis of all patients who underwent TIPS creation from June 1990 to September 1996. SETTING: Academic medical center. PATIENTS: 19 adults who developed severe hyperbilirubinemia (bilirubin level > 171.0 micromol/L) within 1 month after TIPS creation were compared with 213 adults who did not develop hyperbilirubinemia after TIPS creation. INTERVENTION: TIPS creation. MEASUREMENTS: Laboratory measures and clinical outcomes. RESULTS: According to laboratory indices, hemolysis was unlikely to have occurred. By 90 days, 95% of patients with hyperbilirubinemia had died or had undergone liver transplantation compared with 17% of controls (P < 0.001). Predictors of hyperbilirubinemia included nonalcoholic causes of liver disease (P = 0.01) and a pre-TIPS prothrombin time of 17 seconds or more (P = 0.016). CONCLUSIONS: Severe hyperbilirubinemia after TIPS creation heralds a high risk for death or need for liver transplantation. Reduced hepatic reserve predicts the development of hyperbilirubinemia.

Thrombopoietin levels in patients with cirrhosis before and after orthotopic liver transplantation.

BACKGROUND: Thrombocytopenia is a common manifestation of cirrhosis. OBJECTIVES: To determine plasma thrombopoietin levels in cirrhotic patients with thrombocytopenia, monitor those levels before and after orthotopic liver transplantation, and compare thrombopoietin messenger RNA (mRNA) levels in liver samples from cirrhotic patients and controls. DESIGN: A cross-sectional study of patients with cirrhosis, including a small subset of patients who had orthotopic liver transplantation. SETTING: University-affiliated hospital. PATIENTS: 44 patients with cirrhosis, including 17 patients who had orthotopic liver transplantation. INTERVENTION: Orthotopic liver transplantation. MEASUREMENTS: Plasma thrombopoietin levels in all patients, platelet counts in all patients, and thrombopoietin mRNA levels in liver samples from nine patients with cirrhosis and eight controls. RESULTS: Thrombopoietin levels were undetectable in 39 of 44 patients with cirrhosis. In 16 of 17 patients, the levels became detectable after liver transplantation. Thrombopoietin mRNA levels were decreased in liver samples from patients with cirrhosis compared with controls (P = 0.0103). CONCLUSIONS: The low thrombopoietin levels in cirrhotic patients with thrombocytopenia and the increased levels after orthotopic liver transplantation suggest that impaired production of thrombopoietin may contribute to thrombocytopenia associated with cirrhosis.

A controlled analysis of the transjugular intrahepatic portosystemic shunt in liver transplant recipients. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Liver Transplantation Database.

BACKGROUND: The transjugular intrahepatic portosystemic shunt (TIPS) is an important treatment for complications of portal hypertension. As some authors have suggested that TIPS may facilitate liver transplantation technically, the objective of this study was to determine the impact of TIPS on the liver transplant operation and its outcome. METHODS: The analysis was designed as a retrospective cohort study using a multicenter database. Fifty-five patients with TIPS were matched with 55 controls on the basis of 10 pretransplant laboratory, clinical, and demographic features. TIPS patients and control patients were compared with regard to duration of surgery, intraoperative blood product usage, liver and renal function, volume of ascites, survival, and hospital stay. For confirmatory purposes, a parallel analysis using linear regression methods was performed. RESULTS: By matched analysis, TIPS patients had less ascites at surgery (mean 0.9+/-0.20 vs. 2.2+/-0.37 L, P=0.005) and a slightly shorter time from incision to cross-clamp (mean 2.1+/-0.10 vs. 2.5+/-0.15 hr, P=0.03). However, there were not significant differences for total operative time (mean 6.0+/-0.17 vs. 6.3+/-0.25 hr, P=1.00), blood product usage, or any other outcome variable. Regression analysis confirmed these results. CONCLUSIONS: TIPS does not significantly impact the course of liver transplantation surgery. Therefore, preoperative portal decompression solely to facilitate liver transplantation is not an appropriate indication for TIPS.

Transjugular intrahepatic portosystemic shunts (TIPS) in children.

The transjugular intrahepatic portosystemic shunt procedure is an accepted treatment for adults with complications of portal hypertension. We performed a retrospective review of all pediatric TIPS placements performed at the University of California, San Francisco between 1990 and 1996. Twelve procedures were attempted in nine children, with a mean age (+/- SD) of 9.4 +/- 3.9 years (range, 5 to 15 years) and a mean weight of 31 +/- 18 kg (range, 16 to 70 kg). The indications for TIPS placement were portal hypertension complicated by chronic variceal hemorrhage not controlled with sclerotherapy (n = 7) and hypersplenism with thrombocytopenia (n = 2). TIPS placement was successfully completed initially in seven of nine (78%) patients. Unfavorable vascular anatomy was the cause of failure in two cases. The seven patients who underwent successful TIPS placement were followed up for an average of 136 days (range, 1 to 800 days); two still have patent shunts, three underwent liver transplantation, one had a splenorenal shunt after stenosis, and one died of underlying liver disease. Variceal bleeding was controlled in four of five patients who successfully underwent TIPS placement. Shunt occlusion occurred in four patients; patency was restored by transjugular shunt revision in three, and a splenorenal shunt was performed in one.

Fibrosing cholestatic hepatitis in renal transplant recipients.

Fibrosing cholestatic hepatitis in a specific histologic manifestation of hepatitis B virus infection consisting of periportal fibrosis, hepatocyte ballooning, cholestasis, a relatively scant inflammatory infiltrate, and marked overexpression of hepatitis B viral antigens in hepatocytes. Until recently, fibrosing cholestatic hepatitis had been reported only in recipients of liver allografts. In this report, we present two patient in whom this lesion developed following renal transplantation. Both patients had previous liver biopsies showing relatively mild histologic changes. In one patient, the lesion developed early after retransplantation, during the period of maximal immunosuppression. However, in the second patient this lesion developed after withdrawal of immunosuppression. In both cases, death occurred within a few months because of progressive liver disease. Since this lesion can develop in "relatively healthy" hepatitis B carriers following transplantation of organs other than liver, these patients should have careful monitoring of their liver disease. Moreover, since the disease may progress despite withdrawal of immunosuppression, these patients would clearly benefit from the development of more effective therapies for posttransplant hepatitis B.

Incidence and significance of Aspergillus cultures following liver and kidney transplantation.

Aspergillus infection is a rare but devastating complication following solid organ transplantation, with mortality rates that approach 100%. Aspergillus species (sp) are also ubiquitous in our environment and may contaminate culture plates. To determine the significance of positive Aspergillus cultures, we analyzed all positive cultures from the liver and kidney transplant services at our center for the treatments used and clinical outcomes. Aspergillus sp. were cultured from 4.5% of liver and 2.2% of kidney transplant recipients. A. fumigatus was the most common isolate, followed by A. niger and A. flavus. The lung was the most common site of positive cultures. Body fluids (ascites, pleural fluid) were common sources of positive cultures but were never associated with clinical disease. Positive brain biopsies occurred in 10% of patients. Analysis of risk factors for significant infection revealed that cultures with >2 colonies or more than one site of infection were predictive of significant infection and portended a poor prognosis even with aggressive therapy. Two or fewer colonies from a single site likely represented contamination and may be followed with repeat cultures. The high mortality rate associated with Aspergillus sp. infections in transplant recipients highlights the need for better anti-fungal prophylaxis and treatment.

The use of the T tube after orthotopic liver transplantation.

An end-to-end choledochocholedochostomy (CD) over a T tube or a Roux-en-Y choledochojejunostomy (CDJ) have been the standard method of biliary reconstruction following orthotopic liver transplantation (OLTx). The objective of this study was to assess whether or not use of the T tube leads to increased biliary tract complications. Biliary tract complications were categorized as bile leak, stenosis, or obstruction that required therapeutic intervention. OLTx was performed in 161 patients over an 18-month period. Fifty-one patients were excluded from the study leaving a total of 110 patients for evaluation. Fifty-nine had their bile duct reconstructed over a T tube (CD T tube, group I) while the remaining 51 patients underwent bile duct reconstruction without a T tube (CD, group II). No difference was noted between groups I and II in their survival rate, rate of conversion to Roux-en-Y CDJ, or biliary complication rates. Our results indicate that CD (i.e., without a T tube) is both a safe and effective technique to reconstruct the biliary tract following hepatic transplantation. Routine use of a T tube with a CD anastomosis is unnecessary in most liver transplant patients. In addition, the omission of a T tube has reduced the number of radiological procedures performed at our center.

Successful reversal of hepatic encephalopathy with intentional occlusion of transjugular intrahepatic portosystemic shunts.

PURPOSE: To establish a safe and effective method for occluding a transjugular intrahepatic portosystemic shunt (TIPS) in patients who develop uncontrollable, disabling encephalopathy. PATIENTS AND METHODS: The study population consisted of five patients who developed refractory encephalopathy following TIPS. The indication for TIPS was bleeding in four patients and ascites in one. Wallstents that were 10 mm in diameter and 68 mm long were used to bridge the hepatic parenchyma in all patients. The onset of encephalopathy from the time of the TIPS procedure ranged from 24 hours to 210 days. Because encephalopathy was not responsive to conventional medical management, shunt thrombosis was induced by means of temporary inflation of an 11.5-mm-diameter latex occlusion balloon within the midportion of the stent. RESULTS: All shunts were successfully thrombosed when the balloon was inflated for 12 hours or more. Encephalopathy resolved in four patients and improved in the remaining patient. One patient experienced recurrent bleeding within 24 hours of the TIPS occlusion that was controlled medically. CONCLUSION: Temporary occlusion of a TIPS with latex balloons successfully induces shunt thrombosis and improves encephalopathy. However, the patient is again exposed to risks related to complications of portal hypertension.

Hemodynamic consequences of therapeutic portosystemic shunting: recent experience with transjugular intrahepatic portosystemic shunts.

TIPS provides a side-to-side portosystemic shunt without a major abdominal operation. Although TIPS is relatively less invasive, it is associated with similar hemodynamic alterations as surgically created side-to-side shunts. An important difference is that a mild degree of portal hypertension is maintained with TIPS similar to small diameter shunts. TIPS provides effective portal decompression and prevents variceal hemorrhage. However, the risk of encephalopathy is relatively high and stenosis is a long-term concern in many patients. An important advance in the future use of TIPS will be tailoring the diameter of the shunt to optimize regional and systemic hemodynamics in a given individual to minimize the risk of bleeding or to decrease ascites accumulation while limiting the risk of hepatic encephalopathy and liver failure.

Two-year outcome following transjugular intrahepatic portosystemic shunt for variceal bleeding: results in 90 patients.

BACKGROUND/AIMS: Transjugular intrahepatic portosystemic shunt (TIPS) is a new therapy for variceal bleeding. Immediate technical and short-term clinical results have been reported. This study was undertaken to evaluate mid-term outcome after TIPS in patients who successfully underwent the procedure for variceal bleeding. METHODS: Ninety patients were followed up prospectively by clinical examination and radiological shunt evaluation including Doppler sonography and transjugular portal venography. RESULTS: The average follow-up in surviving patients was 2.2 years. The cumulative survival rate was 60% at 1 year and 51% at 2 years. The rate of cumulative rebleeding was 26% at 1 year and 32% at 2 years. A shunt abnormality was noted in all rebleeding patients. Rebleeding was successfully controlled in all but 1 of the patients who underwent shunt revision. Cumulative detection of stenosis or occlusion was 31% at 1 year and 47% at 2 years. Thirty-eight percent of shunt abnormalities were detected by routine surveillance. Percutaneous shunt revision was attempted in 22 patients and was successful in 21 (95%). CONCLUSIONS: Although mid-term primary patency is limited in many patients by the development of a shunt stenosis or occlusion, shunt function can be maintained in most patients by careful surveillance and periodic percutaneous intervention.

Hepatic encephalopathy after transjugular intrahepatic portosystemic shunts: incidence and risk factors.

OBJECTIVES: The aim of this study was to determine the incidence of new or worsened hepatic encephalopathy after transjugular intrahepatic portosystemic shunts (TIPS) and to ascertain which clinical characteristics are associated with this complication. METHODS: At the University of California, San Francisco, over 22 months, TIPS were placed successfully in 108 adults. Seventy-seven patients in whom it was possible to assess the development of encephalopathy comprised the study population. Clinically significant encephalopathy was assessed at protocol clinic follow-up and, in some cases, by phone contact with the patient and the referring physician. Post-TIPS encephalopathy was defined as new onset of clinical encephalopathy requiring treatment or worsening of preexisting encephalopathy within 1 yr of TIPS. RESULTS: The overall incidence of new or worsened encephalopathy was 23% (18/77). Post-TIPS encephalopathy was well controlled with lactulose in 78% of cases and was progressive in 22%. Multivariate analysis showed that an increased risk of encephalopathy was associated with an etiology of liver disease other than alcohol [relative risk (RR) 9.2, p = 0.0052], female gender (RR 3.0, p = 0.029), and hypoalbuminemia (RR 2.2 for each 1 g/dl decrease, p = 0.044). CONCLUSIONS: Hepatic encephalopathy is a common complication of TIPS that can be controlled medically in most patients. The identification of clinical variables associated with an increased risk of encephalopathy may be useful in the selection of appropriate candidates for this procedure.