Search

The TIPS clearly has had a major impact on the treatment of complications of portal hypertension in the cirrhotic patient. Currently, TIPS is performed in community hospitals as well as university centers in the United States. While the shunt is placed under local anesthesia in a nonoperative fashion, it must be remembered that it does function as a highly effective side-to-side shunt with its attendant complications including hepatic encephalopathy and occasional liver failure. Early reports of clinical and hemodynamic results after TIPS have clearly demonstrated it to be an effective bridge to liver transplantation. Nonetheless, transplantation candidates who experience their initial episode of variceal hemorrhage still should be managed with sclerotherapy or variceal band ligation. However, if bleeding recurs during a course of treatment or cannot be acutely controlled, TIPS has proved invaluable in stabilizing patients prior to liver transplantation. Refractory variceal bleeding in Child's class C patients, in whom the perioperative mortality associated with surgical shunts is high, is also reasonable indication for TIPS. Potential, but less well-proved indications for TIPS include refractory ascites, hepatic hydrothorax, and the Budd-Chiari syndrome. Refractory variceal hemorrhage in Child's class A or B patients, bleeding from portal hypertensive gastropathy, and HRS represent possible, but unproved, indications. Preoperative reduction in portal hypertension prior to liver transplantation does not appear to represent an appropriate indication for TIPS. In spite of the wide acceptance of TIPS, it will be important to continue to study its indications and its complications so that it can be optimally used in the treatment of patients with portal hypertension.

Renal insufficiency (RI) is a common finding with end-stage liver disease. RI is generally not regarded as a contraindication to liver transplantation. However, the impact of RI on outcome following transplantation and the role of combined liver-kidney transplant are not well understood. The effect of RI on patients with fulminant hepatic failure (FHF) or chronic liver disease (cirrhosis) was investigated using the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Liver Transplantation Database. Patients were analyzed based on the presence of RI, defined as creatinine >1.6 mg/dl, or on dialysis. Patients undergoing liver-kidney transplantation were analyzed separately. For patients with FHF, the RI group had a lower patient survival rate at 1 year (50% vs. 83%, P=0.04) and tended to have a lower graft survival rate (50% vs. 71%). Stay in the intensive care unit (ICU) was prolonged in the RI group but hospital stay was not. Among patients with cirrhosis, RI did not affect patient survival, except for patients on dialysis or those with liver-kidney transplants. One-year patient and graft survival rates were 65% and 60% for the dialysis group, 74% and 70% for the liver-kidney transplant group, 89% and 86% for RI patients not on dialysis, and 89 and 84% for non-RI patients. ICU and hospital stays were prolonged for all of the RI groups compared with the non-RI patients. Patients with RI had higher rates of posttransplant dialysis; however, the differences tended to equalize after 4 weeks. We conclude that RI in FHF and RI requiring dialysis or liver-kidney transplantation in cirrhosis predict lower posttransplant patient and graft survival rates. Patients with RI have longer hospital and ICU stays and an increased need for dialysis, which likely increases the cost of transplantation. Whether liver-kidney transplantation improves outcome and thus represents an appropriate use of cadaver kidneys requires further study.

To evaluate the hepatic regenerative response in patients with alcoholic liver disease, sera from 263 patients with severe alcoholic hepatitis and/or cirrhosis were analyzed for hepatocyte growth factor (HGF) and alpha-fetoprotein (AFP). HGF concentration was elevated above healthy controls in 95% of the patients (median level = 2.4 ng/ml), whereas AFP tended to be depressed below controls (median level = 4.1 ng/ml). Correlations with parameters of liver injury (i.e., ascites, encephalopathy, AST bilirubin, and protime) all showed a more significant correlation with HGF concentrations than those of AFP. Patients with HGF levels below the mean (4 ng/ml) exhibited significantly better survival (median survival = 35 months vs. 8.5 months for those with HGF > or = 4 ng/ml; p = 0.007). Serum HGF levels were associated with various specific histologic features of alcoholic hepatitis that included, but were not exclusively related to, necrosis.

Prophylactic hepatitis B immunoglobulin (HBIg) reduces the risk of reinfection in hepatitis B surface antigen (HBsAg)-positive liver transplant recipients. In the medical center of this study, high-dose HBIg immunoprophylaxis is administered at a fixed dose of 10,000 IU monthly, and in this study, the long-term efficacy of this treatment regimen was examined. Of 52 HBsAg-positive liver transplant recipients, 24 were administered HBIg immunoprophylaxis, and 28 were administered no specific therapy; the 2-year recurrence rates (defined by the reappearance of HBsAg) were 19% and 76%, respectively. Fifty-four percent of the HBIg-treated patients were positive for HBeAg or hepatitis B virus (HBV) DNA (by hybridization assay) pretransplantation. In patients administered monthly HBIg, intrapatient and interpatient variability in trough antibody to HBsAg (anti-HBs) titer was significant, highlighting the potential difficulties of using anti-HBs titer to guide therapy. Trough anti-HBs titers were less in patients who became HBsAg positive than in patients who remained HBsAg-negative (490 vs. 1290 mIU/mL) (P = .0001), reflecting either the cause or effect of HBV reinfection. Of 9 patients who remained HBsAg-negative and who were administered monthly HBIg for at least 1 year, HBV DNA by polymerase chain reaction amplification was detectable in the sera of 67%, the lymphocytes of 50%, and the liver of 57%. In conclusion, a fixed monthly dose of HBIg reduces the recurrence of HBs antigenemia, even in patients with indices of active viral replication pretransplantation. The presence of residual virus in the majority of patients administered HBIg suggests that long-term HBIg administration may be necessary.

Whether primary biliary cirrhosis (PBC) recurs after liver transplantation has remained an interesting and controversial issue; rejection, viral hepatitis, and drug effects all may mimic recurrent PBC histologically and biochemically. Furthermore, reliable clinical criteria for PBC recurrence are lacking. In this study, the issue of disease recurrence using a well-characterized monoclonal antibody (MAb), C355.1, that reacts with the immunodominant mitochondrial autoantigen of PBC (pyruvate dehydrogenase complex [PDC-E2]) was addressed. When used in an immunohistochemical assay, C355.1 produces intense apical staining of bile duct epithelium specifically in liver sections of patients with PBC and may be the earliest known marker of PBC. Immunohistochemical and histological analysis of serial liver biopsy specimens of 67 patients pre- and post-orthotopic liver transplantation (OLT), including 38 patients with PBC and 29 non-PBC liver disease controls, was performed. Sections were stained with MAb C355.1 or the control MAb C315 and analyzed to determine whether there was a recurrence of apical reactivity in the bile ducts of the posttransplantation biopsy specimens. The immunohistochemical staining was correlated with the histological findings and serum biochemistries at the time of the biopsy. Our data indicate that a significant number of patients who underwent transplantation for PBC (28 of 38) but not controls (0 of 29) develop a staining pattern of liver bile duct epithelium with MAb C355.1 that is indistinguishable from the pretransplantation pattern. Of the 28 patients with this apical staining pattern, 8 were characterized histologically as possible recurrent PBC, 2 as chronic rejection, 2 as acute rejection, 9 as nonspecific changes, 4 as normal or near normal, and 3 had other histological changes. Only 50% of the patients with apical C355.1 staining had liver enzyme levels suggestive of cholestasis. Thus, there appears to be immunohistochemical evidence that supports the concept of recurrence of PBC after OLT. The appearance of biliary epithelial abnormalities before the clinical appearance of disease is important not only for liver transplantation but also for understanding the natural history of PBC.

Infection with hepatitis C virus (HCV) genotype 1b has been reported to be associated with more severe posttransplantation liver disease than infection with non-1b genotypes. To address this issue, we evaluated the outcome in 124 patients who underwent liver transplantation for chronic HCV infection. The HCV genotype and/or serotype responsible for infection was determined by four different methods. HCV RNA was detected in serum samples by polymerase chain reaction (PCR) amplification, and quantified by branched DNA assay. Disease severity was expressed as a histological score (which included grading of portal inflammation, lobular activity, fibrosis, and cytopathic changes). Median duration of histological follow-up was 25 months (range 1-75 months). Genotype was assignable in 112 (92.5%) patients. Genotypes responsible for infection were as follows: 1a = 32.2%, 1b = 27.3%, 2a = 7.4%, 2b = 8.3%, 3a = 14%, and mixed infection (more than one subtype) = 3.3%. Level of viremia, alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, and total histological score were not significantly different in patients infected with type 1b compared with patients infected with other genotypes. While duration of histological follow-up was greater in patients infected with type lb versus other types (P = .02), by univariate and multivariate analysis neither HCV genotype (lb versus others), level of viremia nor duration of histological follow-up were associated with disease severity. Moreover, there was no significant difference in the actuarial graft survival in patients infected with type lb compared with that of patients infected with non-lb types (82% and 87% at 3 years, respectively). Reanalysis using HCV genotype 1 showed no association with disease severity, graft survival, and patient survival. We conclude that HCV genotype 1 and subtype 1b are not associated with disease severity or graft survival in liver transplantation recipients.

Objective: Living-related liver transplantation (LRLT) has established efficacy in children. In a larger recipient, LRLT requires the use of a small graft because of limits on the donor hepatectomy., Summary Background Data: The minimum graft weight required for successful transplantation has not been well established, although a characteristic pattern of graft dysfunction has been observed in our patients who receive small grafts. The authors present a clinicopathologic study of small liver grafts obtained from living donors., Methods: Clinical and histologic data were reviewed for 25 patients receiving LRLT. In five older recipients (small group), the graft represented 50% or less of expected liver weight, whereas in 20 others (large group), the graft represented at least 60% of expected liver weight. A retrospective analysis of graft function was conducted by analyzing clinical parameters and histology., Results: In the small group, 2 of 5 grafts (40%) were lost due to poor function, leading to one patient death (20% mortality), whereas in the large group, 2 of 20 grafts (10%) were lost due to arterial thrombosis without patient mortality. Early ischemic damage related to transplant was comparable with aspartate aminotransferase 203 +/- 23 (small group) and 290 +/- 120 (large group) at 24 hours (p = not significant). Early function was significantly decreased in the small group, with prothrombin time 18.2 +/- 2.2 seconds versus 14.8 +/- 1.6 seconds (large group) on day 3 (p = 0.034). All small group patients developed cholestasis with significantly increased total bilirubin levels at day 7 (16 +/- 5.2 mg% vs. 3.7 +/- 2.7 mg%; p = 0.021) and day 14 (12.0 +/- 7.4 vs. 1.8 +/- 0.7; p = 0.021) compared with the large group. Protocol biopsies in the small group revealed a diffuse ischemic pattern with cellular ballooning on day 7, which progressed to cholestasis in subsequent biopsies. Large group biopsies showed minimal ischemic changes. Three small group patients recovered with normal liver function by 12 weeks., Conclusions: Clinical recovery after a small-for-size transplant is characterized by significant functional impairment associated with paradoxical histologic changes typical of ischemia. These changes apparently are due to graft injury, which can only be the result of small graft size. These findings have significant implications for the extension of LRLT to adults.

In a recently introduced rodent model of nicotine abstinence syndrome the observed behavioral signs closely resembled those typical of rat opiate abstinence syndrome. Nicotine-induced release of endogenous opioids may contribute to nicotine dependence; morphine potently reverses nicotine abstinence signs, while naloxone precipitates abstinence signs and prevents nicotine from alleviating them. Considerable evidence suggests that neuropeptide FF, an endogenous antiopiate peptide, contributes to opiate dependence. Third ventricle injection of neuropeptide FF precipitates abstinence syndrome in morphine-dependent rats, as does SC injection of its lipophilic analogs, dansyl-PQRFamide and dansyl-RFamide. Might NPFF also play a role in nicotine dependence? In the present study, SC injection of 15 or 25 mg/kg dansyl-RFamide or vehicle alone dose dependently precipitated an abstinence syndrome in nicotine-dependent rats. There was a significant, p < 0.01, positive linear trend of abstinence signs as a function of dose. Categories of abstinence signs had the same rank ordering by frequency as observed in spontaneous nicotine abstinence. Injection of 25 mg/kg dansyl-RFamide SC had no significant effect in nondependent rats.

Liver failure, especially in its acute form, is a medical emergency that quickly leads to failure of multiple other organs. Many of these end-organ failures can be supported temporarily by drugs or medical devices, but the support is invariably short-lived if liver function is not restored. In most instances, liver function can only be restored by transplantation, although patients with acute disease have the potential to recover by regeneration ("spontaneous recovery"). Unfortunately, spontaneous recovery from acute liver failure is uncommon, so the two most important aspects of patient management are highly skilled intensive care and early recognition of patients in need of liver transplantation. Even under these circumstances, the mortality of liver failure remains high because we have no easy way of replacing liver function on demand and donor organs are becoming increasingly difficult to obtain in time. The development of techniques for liver assist offer the possibility that patients with liver failure will become a simple management problem, analogous to the options available in the treatment of acute and chronic renal failure.

Reinfection with hepatitis B virus (HBV) after liver transplantation is nearly universal in patients not receiving immunoprophylaxis. Because reinfection reduces graft and patient survival, treatment of recurrent infection is important. Interferon alfa (IFN-alpha) is an effective therapy for chronic hepatitis B infection in immunocompetent patients, but its efficacy in transplant recipients has not been established. Fourteen liver transplant recipients with recurrent hepatitis B infection (hepatitis B surface antigen [HBsAg] positive in serum; hepatitis on biopsy) were treated with IFN-alpha 2b (Intron A; Schering Inc, Kenilworth, NJ) 3 million units (MU) three times weekly for 23.5 weeks (median, range 4 to 41). The primary endpoint was loss of HBV DNA by the b-DNA assay (a virological response). Before treatment, all patients were HBV DNA positive and 9 were hepatitis B e antigen (HBeAg) positive. Pretreatment HBV DNA levels were 6,760 MEq/mL (median, range 2.0 to 11,888 MEq/mL). HBV DNA levels decreased significantly with treatment (P = .03). Four patients had a complete and sustained virological response. Virological responses did not consistently correlate with biochemical response because of concomitant hepatitis C. Two patients had a serological response; 1 lost HBeAg, another lost HBeAg and HBsAg. All responders remained HBV DNA negative in follow-up (mean, 32 months; range, 23 to 40), but 1 patient required retransplantation for cirrhosis. Of the nonresponders, 1 patient required retransplantation for chronic rejection, 3 required retransplantation for recurrent hepatitis B, 3 died with recurrent hepatitis B, and 3 are alive and remain HBV DNA positive. IFN-alpha can induce a sustained serological (14%) and virological response (29%) in liver transplant recipients with recurrent HBV infection.

Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are common complications after orthotopic liver transplantation (OLT), but the liver pathology and clinical outcomes of HBV infection with HCV coinfection have not been thoroughly examined. In this study, we used the polymerase chain reaction (PCR) to detect HBV and HCV in pre- and post-OLT sera of 38 patients and correlated the findings with clinical outcome and liver pathology. Of 13 patients who were HBV and HCV negative before OLT, 9 acquired HBV infection, and 4 developed acquired HBV and HCV coinfections after OLT. Persistent HBV infections were present in 10 patients. Three patients with pre-OLT HBV infections developed persistent HBV and acquired HCV coinfections after OLT; 5 with pre-OLT HCV infections developed acquired HBV and persistent HCV coinfections after OLT, and 7 had persistent HBV and HCV coinfections before and after OLT. Portal/periportal inflammation was the same in all groups; however, lobular inflammation and fibrosis were more severe in patients with persistent HBV infections and in those with acquired HBV and HCV coinfections. Two major histopathological patterns were present in patients with HBV and HCV coinfections, one with predominant features of HCV infection, and the other with those of HBV infection. Patients with post-OLT HBV and HCV coinfections had survival rates similar to those with acquired HBV infection, whereas patients with persistent HBV infections experienced more allograft loss caused by chronic hepatitis or fibrosing cytolytic hepatitis, and had a more dire clinical outcome than the others. Although the limited numbers reported in this study prevent a definitive conclusion, our data suggest that in patients with HBV and HCV coinfections, the presence of HCV may improve the clinical outcome as compared with the expected outcome of persistent HBV infection alone.

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.

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.

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.

In a recently introduced rodent model of nicotine abstinence syndrome, the observed signs closely resembled those typical of rat opiate abstinence syndrome. Signs were precipitated by naloxone and potently reversed by morphine as well as nicotine itself, suggesting that nicotine might relieve nicotine abstinence syndrome through releasing endogenous opioids. To test this hypothesis, rats were continuously infused subcutaneously (SC) for 7 days with 9 mg/kg per day nicotine tartrate. Each rat was observed for abstinence signs at 18 and 21 h after termination of infusion. Three minutes before the 21-h test, all rats received 0.35 mg/kg nicotine tartrate, SC; 5 min before the nicotine injection, subjects received 9 or 4.5 mg/kg naloxone or saline alone, SC. Abstinence reversal scores were calculated as signs at 21 h as a percentage of signs at 18 h. Naloxone prevented nicotine alleviation of nicotine abstinence in a dose-related manner. However, naloxone in the absence of a nicotine injection had no effect on abstinence severity in either highly dependent or moderately dependent rats (infused with 9 or 5 mg/kg per day nicotine tartrate, respectively). These results support the hypothesis that endogenous opioids play a role in nicotine dependence and abstinence.

Neuropeptide FF (NPFF) has certain antiopiate actions and may play a role in opiate tolerance and dependence. Third ventricle injection of 10 micrograms NPFF induces a quasimorphine abstinence syndrome in opiate-naive rats. Nitric oxide synthesis may also contribute to opiate tolerance and dependence. The present study tests the hypothesis that NPFF acts through stimulation of nitric oxide synthase (NOS). Third ventricular injection of 10 micrograms NPFF precipitated an average of 46 abstinence-like signs during a 20-min observation. Pretreatment (30 min earlier) with 7.5 or 15 mg/kg s.c. of the NOS inhibitor nitro-L-arginine (L-NNA) resulted in a significant and dose-dependent alleviation of NPFF-induced abstinence-like signs. The anti-NPFF activity of 15 mg/kg L-NNA was blocked by 750 mg/kg L-arginine, but not by the same amount of D-arginine, indicating that L-NNA attenuates NPFF activity through a stereospecific inhibition of NOS.

FMRFamide is a molluscan peptide that has shown antiopiate activity in a number of mammalian test systems. Peptidomimetics of FMRFamide substituted with conformationally constrained stereoisomers of Z-2,3-methanomethionine or E-2,3-methanomethionine precipitated abstinence syndrome far more potently than FMRFamide itself. The current study determined the effect on antiopiate potency of an additional rigid substitution. A peptidomimetic containing a stereoisomer of E-2,3-methanomethionine was compared with a peptidomimetic additionally substituted at the C-terminal with E-2,3-methanophenylalanine. Morphine abstinence signs were observed after varying doses (0.125-25.0 micrograms) of these two peptidomimetics were injected into the third ventricle of morphine-dependent rats. The peptidomimetic containing both rigid substitutions was far more potent than the peptidomimetic of FMRFamide containing methanomethionine alone. The increased potency appears to be related to enzyme resistance rather than receptor affinity.

To determine the best method for detecting HCV infection in immunosuppressed patients, stored frozen serum from 101 liver transplant recipients was tested for hepatitis C virus. Each sample was tested by four assays. HCV RNA was detected by both polymerase chain reaction (PCR) and branched DNA signal amplification. Antibody to HCV was determined using second-generation enzyme-linked immunoassay (EIA) and recombinant immunoblot assay. Forty one transplant recipients met the working definition for true positives of HCV infection. Of these "true positives," 98% were positive by HCV RNA PCR assay, 88% by b-DNA signal amplification assay, 88% by anti-HCV EIA, and 63% demonstrated two or more reactive bands on recombinant immunoblot. Five of 57 (9%) HCV-antibody negative recipients had HCV RNA detected by both methods. Of 44 HCV enzyme-linked immunoassay (EIA) repeatedly reactive samples, the recombinant immunoblot was negative in 2 and indeterminate in 13. HCV RNA was present in 9 of 13 recombinant immunoblot indeterminate sera. Nine EIA repeatedly reactive sera were negative by both tests for HCV RNA. In liver transplant recipients, HCV infection is best determined by measurement of HCV RNA. Antibody formation may be delayed or suppressed in a minority of patients despite > 10(9) equivalents/L (> 10(6)/mL) of HCV RNA in serum. Recombinant immunoblots with a single reactive band pattern often indicate HCV infection in immunosuppressed patients.

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

Liver granulomas have long been known to pose diagnostic problems for pathologists; however, their prevalence and associated etiologic factors have not been studied in liver transplant patients. We reviewed 3632 liver biopsy specimens from 563 patients at two institutions and identified 42 patients with posttransplant granulomas. A possible or probable etiologic factor was identified in 30 (71%) cases. Most were epithelioid granulomas and microgranulomas located in the parenchyma associated with hepatocyte necrosis (21 cases, 50%). Portal-based granulomas were associated with recurrent primary biliary cirrhosis (5 cases, 12%), acute cellular rejection (2 cases, 4.8%), and a foreign body-type reaction (1 case, 2.4%). One case was associated with tuberculosis (2.4%), 4 cases occurred in a fatty liver (9.5%), and 8 patients had liver granulomas but no other significant abnormality. The granulomas were most frequent in the first 7 months after transplantation when the patients were biopsied more often and underwent episodes of rejection or acute hepatitis. Portal-based granulomas in this period were usually associated with acute cellular rejection. After 7 months, the frequency of granulomas as well as the number of biopsies decreased and portal-based granulomas associated with recurrent primary biliary cirrhosis were most common (5 cases, 12%). Rare, late-appearing parenchymal granulomas were also seen (3 cases) and consisted of 1 lipogranuloma and 2 cases of epithelioid granuloma. The latter were thought, in 1 patient, to be associated with parenchymal hepatocyte necrosis; the others were of unknown etiology.

There is evidence that neuropeptide FF (NPFF) has antiopiate activity and may play a role in opiate dependence and subsequent abstinence syndrome. A fragment of NPFF was modified at the C-terminal in an effort to convert it to an NPFF antagonist. It was also dansylated at the N-terminal in an effort to render it more lipophilic and increase its penetration of the blood-brain barrier. Third ventricle administration of the resulting compound, dansyl-PQRamide (0.75 microgram and 1 microgram), dose-dependently antagonized the quasi-morphine abstinence activity of NPFF (10 micrograms) in opiate-naive rats. Subcutaneous injection of dansyl-PQRamide (13 mg/kg) in chronically morphine-infused rats attenuated opiate dependence as indicated by prevention of naloxone-precipitated abstinence syndrome. Dansyl-PQRamide displaced radiolabelled ligand from NPFF receptors in a concentration-dependent manner with a Ki of 13 microM, and had a half-life over 300 times longer than NPFF under aminopeptidase digestion.

Biliary tract complications represent an important problem after transplantation. They are not only important in the immediate posttransplantation period, but perhaps of even greater importance in the long-term management of transplant recipients. One of the major changes that has occurred over the past several years is an increasing use of nonoperative therapy, either via endoscopic or percutaneous routes. In many cases of biliary leak, stones, and T-tube malposition, nonoperative management may be curative. The exact role they play in the management of strictures, particularly diffuse stricturing and isolated hepatic duct strictures, remains to be determined. At the least, it provides temporary drainage before initiating surgical therapy. In addition to being efficacious, nonsurgical management is quite safe. In 64 cases of biliary complications managed nonoperatively, complications occurred at UCSF in only four patients. One patient developed bleeding along the percutaneous catheter tract and required replacement with a larger diameter catheter to tamponade the bleeding. Two patients developed hemobilia secondary to intrahepatic pseudoaneurysms caused by the percutaneous drainage catheter. One patient developed an osteomyelitis of a rib related to an indwelling percutaneous biliary catheter that responded to antibiotics and rib resection. Finally, understanding several of the biliary complications that occur after transplantation (ie, sphincter of Oddi dysfunction) will require additional research and hopefully will determine the pathophysiology of these complications. This should lead to more rational therapy.

The use of passive immunoprophylaxis to prevent HBV reinfection of the allograft following liver transplantation has led to a dramatic improvement in the outcome of patients who undergo transplantation for chronic hepatitis B. Hepatitis B previously was not one of our favorite diseases for which to perform liver transplantation. However, we now regard patients with this disease as good candidates for liver transplantation. I hope I have presented a compelling argument that no patient with hepatitis B, regardless of serological status, should be a priori denied liver transplantation. Studies from both the U.S. and Europe have shown that HBV reinfection can be prevented in almost all patients at a cost not out of line with other accepted indications for liver transplantation. Thus, I once again, ask the question, "Should patients with chronic hepatitis B undergo liver transplantation?" At our institution, the answer is an emphatic Yes!

At the University of California, San Francisco, 17 patients who met the following criteria-hepatic tumor unresectable because of location or inadequate liver reserve, no metastases, HBsAg negative, no tumor larger than 5 cm in diameter, and no more than three tumors--were enrolled prospectively in a protocol employing preoperative chemoembolization to assess whether orthotopic liver transplantation (OLT) could cure a majority of highly selected patients with hepatocellular carcinoma (HCC). Thirteen patients had biopsy-proven HCC, 2 had the fibrolamellar variant, and 2 had radiological findings of HCC but no biopsy confirmation. Fourteen had underlying liver disease. All arteriographically apparent lesions were chemoembolized using a mixture including Gelfoam powder, doxorubicin, mitomycin-c, and cisplatin. Eight patients with poor hepatic reserve were chemoembolized when a donor organ became available, whereas 9 patients were chemoembolized and then placed on the waiting list. The only complication of chemoembolization was a gangrenous gallbladder in 1 patient. Thirteen patients underwent liver transplantation (2 patients without prior histological confirmation of carcinoma had no identifiable tumor at OLT); 3 patients developed metastases between the time of enrollment and donor organ availability and subsequently died; and 1 patient underwent a trisegmentectomy. Ten of the 11 patients with biopsy-proven HCC who underwent transplantation remain free of recurrent cancer at a median of 40 months; 1 patient died at 6 months of lymphoproliferative disease with no cancer found at autopsy. Although the role of chemoembolization is uncertain, these data show that the majority of carefully selected patients with HCC may achieve long-term survival with OLT.

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.

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.

Cirrhosis is frequently complicated by ascites that may become resistant to diuretic therapy. Transjugular intrahepatic portosystemic shunts (TIPS) represent a new treatment for this debilitating condition. The aim of this study was to ascertain the clinical efficacy of TIPS, as well as its impact on renal function and on hormonal parameters. Five inpatients with refractory ascites were studied prospectively before TIPS, and 3 and 14 days after TIPS. After TIPS, ascites completely resolved or was minimal in all patients. Diuretics were discontinued in three subjects and decreased by at least 50% in two. One patient developed liver failure after TIPS and required liver transplantation; the others remained stable after a mean follow-up of 14 months. Mean urinary sodium excretion increased from 2.1 +/- 0.6 mEq/24 hr before TIPS to 13.0 +/- 4.3 mEq/24 hr 14 days after TIPS. Mean serum creatinine and glomerular filtration rate also tended to improve during the study period. With the exception of the patient who developed liver failure, plasma aldosterone concentration decreased from a mean of 126.0 +/- 29.9 ng/dL to 22.8 +/- 6.8 ng/dL (P = .04), and plasma renin activity decreased from a mean of 9.0 +/- 3.0 micrograms/L/h to 0.9 +/- 0.1 microgram/L/h (P = .08). Additionally, 19 patients who underwent TIPS for refractory ascites outside of this protocol were followed prospectively for a mean of 282 days. Clinical improvement in ascites control was noted in 74%, and the mean dose of diuretics was decreased by more than 50%. Nonresponders more often had underlying renal disease. In conclusion, TIPS is an effective therapy for refractory ascites in most patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Liver allografts from HBcAb(+), IgM(-), HBsAg(-) donors can transmit HBV to uninfected recipients. We currently no longer accept these livers for transplantation while continuing to accept the kidneys. The purpose of this study is to determine the risk of donor-transmitted HBV infections from HBcAb(+), HBIgM(-), HBsAg(-) organ donors and determine if the risk of donor-transmitted HBV infections and their severity is dependent on the organ being transplanted. This study consists of a retrospective review of the posttransplant course of recipients of HBcAb(+), HBIgM(-), HBsAg(-) donors accepted at UCSF from 6/85 to 12/93. Transmitted HBV infection was defined as one in which the recipient changed from HBsAg(-) prior to transplantation to HBsAg(+) posttransplant, with no other source. There were 25 of 1190 donors who were HBcAb(+), HBIgM(-), HBsAg(-); 1/42 kidney, 3/6 liver, and 0/7 heart HBsAg(-) transplant recipients of organs from these donors became HBsAg(+) after transplantation. This difference in infection rate (liver vs. kidney and heart) is statistically significant. The clinical course of the liver recipients was also more severe. All of the patients who became infected were HBsAb(-) and HBcAb(-) prior to transplant. We conclude that (1) HBV can be transmitted from HBcAb(+), HBIgM(-), HBsAg(-) organ donors, (2) the rate of transmission is highest and severity of infection is worst in the liver recipients; and (3) we will continue to transplant kidneys from these donors, preferably into immunized recipients.

With appropriate selection criteria, patients with end-stage alcoholic liver disease who undergo orthotopic liver transplantation have similar graft and patient survivals as patients undergoing transplantation for other causes. However, because of the possibility of recidivism after orthotopic liver transplantation there is still reluctance to transplant alcoholic patients. This study examined the association between pretransplant psychosocial variables and the risk of recidivism after orthotopic liver transplantation. At our institution, 43 patients received orthotopic liver transplantation for the referral diagnosis of alcoholic liver disease from February 1, 1988 to May 1, 1991. This represented 17% of all first transplants (43 of 257) performed during this period. Patients were interviewed before orthotopic liver transplantation by a single psychiatrist and responses to a defined set of questions were entered into a clinical database. All 43 patients diagnosed with alcoholic liver disease and a comparison group of patients transplanted for diagnoses other than alcoholic liver disease received a postoperative questionnaire regarding past and present alcohol use. Patients enrolled in the study all had at least 7 mo of follow-up, with the median follow-up being 21 mo. Eighty-six percent of alcoholic liver disease patients (37 of 43) and 86% of patients in the comparison group (37 of 43) of ALD patients agreed to participate in the study. Nineteen percent of alcoholic liver disease patients (7 of 37) and 24% of patients in the comparison group (9 of 37) admitted to having used alcohol after orthotopic liver transplantation, wtih 8% (3 of 37) and 11% (4 of 37) currently using alcohol, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Since the introduction of techniques to reliably identify antibody to the hepatitis C virus and quantitation of hepatitis C virus, there has been an increasing interest in the behavior of chronic hepatitis C infection with liver transplantation. Ninety-seven patients with chronic active hepatitis C and fifty-nine patients with cryptogenic cirrhosis underwent 100 and 62 liver transplantation procedures, respectively, at a single institution. This represents 35% of the total liver transplantations performed during this time period. Twenty-three percent of transplants were performed in patients with evidence of chronic active hepatitis C. Patients and graft survival were excellent in both groups. One-, 2- and 3-yr patient survival rates for chronic active hepatitis C and cryptogenic cirrhosis were 94%, 89% and 87% and 84%, 84% and 73%, respectively. Hepatitis C can frequently be identified after transplantation. More than 95% of patients show persistence of antibody to the hepatitis C virus. Forty-one of 95 patients (surviving > 1 mo) showed recurrent hepatitis (initially seen 3 to 20 mo after transplantation), and 12 progressed to chronic active hepatitis. In 16 patients of the cryptogenic group in whom hepatitis developed, 11 were associated with de novo hepatitis C infection. Seven of these 11 cases went on to a chronic state. Of 11 deaths after transplant in the hepatitis C group, 2 were directly related to recurrent disease. There were 15 deaths in the cryptogenic group, 2 related to de novo hepatitis C. Patients were not serotyped. Interferon therapy was attempted in a small number of patients with disease, with inconclusive results.(ABSTRACT TRUNCATED AT 250 WORDS)

Recently, a rodent model of nicotine abstinence syndrome has been developed based on observing the frequency of spontaneous behavioral signs following termination of continuous subcutaneous infusion of nicotine tartrate. In the present study, the nicotinic antagonist mecamylamine precipitated an abstinence syndrome in nicotine-dependent rats. Twelve rats were each infused for 7 days with 9 mg/kg per day nicotine tartrate in saline via Alzet osmotic minipumps; another 12 rats were sham-operated and remained nicotine-naive. Six rats from each group received 1 mg/kg mecamylamine in saline SC immediately before a 30-min observation, while the remaining six rats from each group received saline alone. Nicotine-infused rats receiving mecamylamine exhibited significantly more (P < 0.01), overall abstinence signs than all other groups. In terms of categories of signs, they displayed significantly more gasps/writhes, teeth chatter/chews, shakes/tremors and ptosis. In a second experiment utilizing only nicotine-naive rats, a far higher dose of mecamylamine (5 mg/kg sc) induced a quasi-nicotine abstinence syndrome. The results provide further validation for this rodent model of nicotine abstinence syndrome.

FHF is an uncommon but devastating condition affecting otherwise healthy persons which causes significant morbidity and mortality. The etiologic factor is most commonly viral infection, with drugs and metabolic disorders being relatively less common causes. Hopefully, newer diagnostic techniques such as PCR will increase our understanding of the causes and pathogenesis of this disorder. Medical management at the present time must focus on anticipating, preventing, and rapidly identifying and treating complications that may affect every major organ system. Encouraging research continues on the clinical application of hepatotrophic drugs and artificial liver support systems, both as potentially definitive therapies and as maintenance for patients awaiting transplantation. Consultation with physicians at a transplant center should be sought early in the course of the patient's hospitalization when OLT is being considered. Liver transplantation has dramatically changed the outlook for patients with FHF, with current survival rates in the 55% to 75% range. The continuing challenge for the transplant team is to allocate available donor organs to those patients who would not otherwise survive, but also to provide OLT in a timely fashion to ensure the best chance of post-transplantation recovery. Newer techniques such as heterotopic liver transplantation, reduced-size organ transplantation, and the utilization of living related donors may further improve the survival of these patients.

FMRFamide is a molluscan peptide that has shown antiopiate activity in a number of mammalian test systems. The current study determined the antiopiate potency of FMRFamide and two conformationally constrained peptidomimetics of FMRFamide containing stereoisomers of (E)-2,3-methanomethionine. Morphine abstinence signs were observed after varying doses (0.25-25.0 microgram) of these substances were injected into the third ventricle of morphine-dependent rats. Both peptidomimetics were far more potent than FMRFamide itself. In addition, although both peptidomimetics bound with lower affinity than FMRFamide to rat spinal cord receptors for NPFF (the mammalian FMRFamide-like peptide), they were far more resistant than FMRFamide to enzymatic degradation by leucine aminopeptidase.

Aged (24-month-old) rats were treated chronically with methanesulfonyl fluoride (MSF), an acetylcholinesterase (AChE) inhibitor with selectivity for central nervous system AChE, or with injection vehicle alone. Twelve 0.22 mg/kg IP injections were given over 4 weeks. MSF rats showed significantly greater speed and accuracy on a 1 trial/day discriminative reward learning task. The chronic MSF treatment resulted in a 56% decrease in brain AChE activity but no discernable locomotor side effects and no liver damage as indicated by aspartate transferase activity.

Objective: The purpose of this study was to assess outcome after liver transplantation for fulminant (FHF) and subfulminant (SHF) hepatic failure and to determine the factors responsible for outcome., Patients and Setting: Thirty-five patients who underwent 42 liver transplantations for FHF and eight patients who underwent eight liver transplantations for SHF at a large university medical center were followed up for 1 month to 5 years., Outcome Measures: Actuarial patient and graft survival for FHF and SHF were assessed and compared with the outcome for all patients who underwent liver transplantation at the same center over the same period (445 transplants in 420 patients). Patients were treated with intracranial pressure monitoring, aggressive measures to decrease intracranial pressure, and rapid transplantation. Functional status and recurrent disease were additional end points., Results: One-year actuarial patient survival rates for FHF and SHF were 92% and 100%, respectively. Minor neurological sequelae were noted in two patients. Functional status was excellent. Posttransplant hepatitis was present in two patients with an original diagnosis of FHF and acute hepatitis B and in three patients with an original diagnosis of FHF and non-A, non-B, non-C hepatitis., Conclusion: Patients with FHF and SHF can achieve excellent results after liver transplantation. Rapid assessment of candidacy with monitoring of intracranial pressure and aggressive treatment for intracranial hypertension are thought to be essential in the outcome of these patients.

Improvement in liver transplantation over the past decade has resulted in questions regarding indications and contraindications, patient selection, timing, and cost.

One hundred patients underwent transjugular intrahepatic portosystemic shunt (TIPS) creation for variceal bleeding (n = 94), intractable ascites (n = 3), hepatorenal syndrome (n = 2), and preoperative portal decompression (n = 1). Shunts were completed in 96 patients. Portal vein pressure was reduced from 34.5 mm Hg +/- 7.6 (standard deviation) to 24.5 mm Hg +/- 6.2; the residual portal vein-hepatic vein gradient was 10.4 mm Hg +/- 0.9. Acute variceal bleeding was controlled in 29 of 30 patients. Of the 96 patients who underwent successful TIPS creation, 26 have died and 22 have undergone liver transplantation; the remaining 48 patients have survived an average of 7.6 months. Variceal bleeding recurred in 10 patients. Fifteen patients developed shunt stenosis (n = 6) or occlusion (n = 9). Patency was reestablished in eight of the nine occluded shunts. Seventeen patients developed new or worsened encephalopathy. The authors conclude that TIPS creation is an effective and reliable means of lowering portal pressure and controlling variceal bleeding, particularly in patients with acute variceal bleeding unresponsive to sclerotherapy and patients with chronic variceal bleeding before liver transplantation.

Specific therapy should be instituted expeditiously once the diagnosis of a biliary leak has been made in patients who have undergone orthotopic liver transplantation. Controversy exists over whether to use nonoperative or operative management. The results of 325 consecutive orthotopic liver transplants in 297 adult and pediatric recipients were reviewed. The biliary tract was reconstructed using a choledochocholedochostomy anastomosis (254/325 or 78%) or a Roux-en-Y choledochojejunostomy anastomosis (71/325 or 22%). The incidence of biliary leaks was 23% (74/325). Overall, only 3% (10/325) of the orthotopic liver transplant recipients required operative repair of a biliary leak. Biliary leaks occurring in patients with Roux-en-Y choledochojejunostomy anastomoses (9/71 or 13%) commonly required operative repair (6/9 or 67%), whereas leaks that occurred in patients with choledochocholedochostomy anastomoses (65/254 or 26%) seldom required operative repair (4/65 or 6%). All choledochojejunostomy leaks occurred at the anastomosis, whereas choledochocholedochostomy leaks occurred either at the anastomosis (17/254 or 7%) or the T-tube insertion site (45/254 or 18%). Our study confirms that in centers with proficient endoscopic and interventional radiologic support, resolution of biliary leaks in orthotopic liver transplant patients can be achieved with nonoperative management.

The endogenous neuropeptide Tyr-MIF-1 (Tyr-Pro-Leu-Gly-amide) has been shown to counteract various opiate actions. In the current study, third ventricular injection of 35 micrograms Tyr-MIF-1 protected by the enzyme inhibitor bestatin precipitated an abstinence syndrome in morphine-dependent rats, but not in opiate-naive rats. The results raise the possibility that Tyr-MIF-1 might participate in opiate dependence and opiate abstinence syndrome.

Hepatitis B recurrence remains a major problem facing liver transplantation programs. The risk of infection varies depending upon the HBV load. High doses of HBIg may reduce the risk of occurrence but it remains expensive. Finally, apparently new infections may occur posttransplantation, which may have been transmitted by organs or blood from HBsAg (-), HBcAb (+) donors, or may reflect reactivation of latent infections in patients who were HBsAg (-). HCV infections are common in patients undergoing liver transplantation, and HCV infection recurs in > 90% of patients; however, recurrent hepatitis C occurs in less than half of these patients. HCV is not an important cause of fulminant non-A, non-B hepatitis, but appears to be the most common cause of posttransplant hepatitis. So what is in the future? For hepatitis B, we still believe the efficacy of HBIg, and in which patients with hepatitis B HBIg should be used, remains to be defined. The effects of antivirals on posttransplant hepatitis B, as well as in prevention of HBV recurrence, also remain to be determined. In the United States, insurance companies are likely to play an important role in determining the future of transplantation for hepatitis B. Medicare recently excluded patients who were HBsAg (+) from coverage for liver transplantation, and a number of private insurers have subsequently followed suit. For HCV, newer screening tests for the virus are likely to decrease the rate of HCV acquisition following liver transplantation, from the current 35% incidence of HCV acquisition. The impact of antiviral treatment on posttransplant hepatitis remains to be determined and deserves study. Finally, the development of regimens that might allow prevention of recurrent HCV infections in patients undergoing liver transplantation also should be a matter of future study.

Rationale and Objectives: Gadolinium-ethoxybenzyl-DTPA (Gd-EOB-DTPA) is a recently introduced experimental magnetic resonance (MR) contrast agent for hepatic imaging. Although liver enhancement has been investigated in a number of animal models, tolerance evaluations of Gd-EOB-DTPA injection have been limited., Methods: The authors investigated acute hepatotoxicity in an isolated perfused rat liver model, cardiovascular effects in the anesthetized rat, and potential immunogenicity of Gd-EOB-DTPA using detection of specific antibodies., Results: Using perfused rat liver model, no significant deviation could be observed for functional parameters, liver enzymes, or potassium release, comparing Gd-EOB-DTPA to a control, but there was a significant choleresis (+250% bile flow). Hemodynamic effects of Gd-EOB-DTPA were observed after femoral bolus injection, but only with relatively high dosages (0.3-0.5 mmol/kg, 10-fold the likely clinical dose in humans). Experimental conditions, idealized for antibody induction, failed to cause an IgG immune response to Gd-EOB-DTPA in the intact rat., Conclusions: The results further support preliminary conclusions that Gd-EOB-DTPA is a well-tolerated MR contrast agent.