Impact of recipient MELD score on resource utilization.

The model for end stage liver disease (MELD) system prioritizes deceased donor organs to the sickest patients who historically require higher healthcare expenditures. Limited information exists regarding the association of recipient MELD score with resource use. Adult recipients of a primary liver allograft (n = 222) performed at a single center in the first 27 months of the MELD system were analyzed. Costs were obtained for each recipient for the 12 defined categories of resource utilization from the time of transplant until discharge. True (calculated) MELD scores were used. Inpatient transplant costs were significantly associated with recipient MELD score (r = 0.20; p = 0.002). Overall 1-year patient survival was 85.0% and was not associated with MELD score (p = 0.57, log rank test). Recipient MELD score was significantly associated with costs for pharmacy, laboratories, radiology, dialysis and physical therapy. Multivariate linear regression revealed that MELD score was most strongly associated with cost compared to other demographic and clinical factors. Recipient MELD score is correlated with transplant costs without significantly impacting survival.

Infection with Listeria monocytogenes following orthotopic liver transplantation: case report and review of the literature.

Infection with Listeria monocytogenes is rare with a reported annual incidence of 4.4 cases/million individuals. Epidemiological data have identified certain groups to be higher risk of developing listeriosis, including neonates, pregnant women, adults older than 60 years of age, individuals afflicted with hematologic malignancies, acquired immunodeficicency syndrome, cirrhosis, and those receiving corticosteroid therapy and organ transplants. Within this last group, multiple cases have been described following bone marrow and renal transplantation, but only a few following liver transplantation. We report a case of a 66-year-old woman presenting with Listeria monocytogenes bacteremia at 32 months following orthotopic liver transplantation.

Liver transplantation at the University of Texas Health Science Center/University Hospital in San Antonio.

Liver transplantation is the only potentially curative treatment for patients with end-stage liver disease. An extensive medical and psychosocial evaluation is performed in an attempt to determine which patients are likely to have acceptable outcomes with the procedure. The limited number of donor livers relative to patients that need a liver transplant, and the occurrence of significant deaths in the waiting group, has motivated many transplant programs to agree to put living donors at risk to help solve this problem. Other complex operative techniques such as splitting livers for use in 2 patients have improved the organ availability for pediatric and adult patients. Growth of a liver transplant program from a small program to a large program necessitates institutional, hospital capacity and infrastructure support at many levels to be successful. This requires a strong partnership between the physicians and the hospital system. 1. The University of Texas Health Science Center/University Hospital in San Antonio has performed 610 liver transplants over ten years. Overall one- and 5-year patient survival rates were 88% and 75%, respectively, despite transplanting a relatively advanced population of patients based on MELD scoring. 2. The most frequent indication for liver transplantation was hepatitis C (52% of patients) and the one-, 5-, and 10-year survival rates for transplantation for hepatitis C was equivalent to survival rates after liver transplantation for other indications, despite significant recurrent hepatitis C liver injury. 3. Technical refinements have decreased operative times and immunosuppressive advances have decreased the side effects while maintaining excellent outcomes. Veno-venous bypass and the placement of biliary T-tubes are not currently used. Standard immunosuppression is lower dose Prograf, Cellcept and steroids with Cellcept being weaned off at 3 months and steroids weaned off by one year. 4. Strategies to increase the donor pool including the use of older donors, the use of steatotic livers, the use of split livers and living liver donors for children and adults are all being used successfully at UTHSCSA.

Steroid elimination 24 hours after liver transplantation using daclizumab, tacrolimus, and mycophenolate mofetil.

BACKGROUND: Corticosteroids have long been a cornerstone of orthotopic liver transplant (OLTx) immunosuppression. Newer, more potent, agents have successfully allowed for more rapid tapering and discontinuation of corticosteroids in OLTx recipients. We hypothesize that corticosteroids can be safely avoided after the first postoperative day (POD) using these newer agents. METHODS: Thirty adult OLTx recipients were prospectively enrolled in a randomized open-label, institutional review board-approved protocol. Fifteen patients (group A) received our standard regimen of tacrolimus, mycophenolate mofetil, and corticosteroids, and 15 patients (group B) received daclizumab, 2 mg/kg on POD 0 and 14, with tacrolimus, mycophenolate mofetil, and corticosteroids on POD 0 and 1 and then discontinuation. In both groups, mycophenolate mofetil was tapered off between 3 and 4 months after OLTx. Bone mineral densitometry was performed at 1, 3, and 6 months after OLTx. Quantitative hepatitis C virus (HCV) polymerase chain reaction was obtained at days 0, 7, 14, 21, and 28. Retransplant recipients, patients with autoimmune hepatitis, or status 1 or 2A patients were excluded. RESULTS: Patient and graft survival rates were 93% (group A) and 100% (group B) with mean follow-up of 18 months. Patients in group B had more rejection diagnosed (25%) compared with group A (6.7%). Yet, the incidence of biopsy-proven acute rejection requiring steroid therapy was 6.7% in both groups. Hispanic race was common in groups A and B (87% and 74%). A total of six biopsies were performed in group B, with three patients having mild rejection responding to an increase in tacrolimus without the need for corticosteroids. One patient in group B was switched to cyclosporine for severe neurotoxicity and remains on monotherapy with normal graft function. No patient in either group developed a requirement for additional antihypertensive medication. Likewise, there were no patients with new-onset diabetes. The bone mineral densitometry was higher in group B at every time point but did not reach statistical significance. Serum cholesterol level was significantly (P=0.03) lower in group B at 6 months after OLTx. Serum triglycerides were also lower, but the difference was not significant. Quantitative polymerase chain reaction for HCV-positive patients (group A, n=7; group B, n=8) frequently increased after OLTx. There was no correlative decrease associated with daclizumab. At present, two patients in group A have documented HCV recurrence. CONCLUSION: Corticosteroids can be safely avoided after POD 1 with the current regimen. With early follow-up, there is no difference in hypertension or diabetes or bone density. Lipid panels tended to be lower in patients who were not on corticosteroids. Longer term follow-up will be needed to demonstrate the potential advantage of corticosteroid avoidance in regard to hypertension, diabetes, and possibly HCV recurrence.

Effect of aspirin on prostaglandin E2 formation and transforming growth factor alpha expression in human rectal mucosa from individuals with a history of adenomatous polyps of the colon.

Colorectal cancer is the second-most frequent cause of cancer mortality in the United States. Human epidemiology and laboratory studies indicate that aspirin may be an effective colorectal cancer chemopreventive agent. This study was designed to determine whether treatment with 81 mg of aspirin per day for 3 months would alter two putative surrogate end point biomarkers of chemoprevention of colorectal cancer [i.e., mucosal prostaglandin E2 (PGE2) formation and transforming growth factor alpha (TGF-alpha) expression] in normal-appearing rectal mucosa from individuals with a history of adenomatous polyps. Rectal biopsies were obtained by flexible sigmoidoscopy at three sequential time points: (a) after a 1-month placebo run-in period (baseline), (b) after 3 months of ingesting 81 mg of aspirin (as a single tablet) once per day, and (c) after 3 months of ingesting a placebo tablet once per day (washout period). Daily aspirin significantly suppressed PGE2 formation, but this significant suppression was completely reversed when aspirin was withdrawn. The extent of TGF-alpha staining in rectal crypts was also reduced significantly (P = 0.039) by daily aspirin. After a 3-month placebo-washout period, however, the mean extent of TGF-alpha staining was not significantly different from either baseline or the aspirin time point. Thus, 81 mg of aspirin daily significantly reduced rectal mucosal PGE2 formation and TGF-alpha expression in patients with a history of adenomatous polyps. These putative surrogate end point biomarkers may be useful intermediate end points in future colorectal cancer chemoprevention trials.

Gallbladder carcinoma producing alpha-fetoprotein.

Alpha-feto protein (AFP) is a clinically useful marker for hepatocellular carcinoma, hepatoblastoma, and nonseminomatous testicular tumors. Elevated serum AFP can also occur with tumors of the gastrointestinal tract, pancreas, lung, kidney, and urachus. Serum AFP can also be minimally elevated in nonmalignant conditions including acute and chronic hepatitis, cirrhosis, and pregnancy. Reports of gallbladder carcinoma that elaborate AFP are extremely rare, and almost all represent papillary carcinomas. Until now, there have been only two reports in the world literature that describe undifferentiated gallbladder carcinoma with elevated serum AFP. The authors present one case of undifferentiated gallbladder carcinoma and another case of poorly differentiated gallbladder carcinoma with increased serum AFP. In both cases, serum AFP was particularly useful in documenting metastatic recurrence of gallbladder carcinoma.

Transforming growth factor alpha distribution in rectal crypts as a biomarker of decreased colon cancer risk in patients consuming cellulose.

Data from rat experimental carcinogenesis studies indicate that supplemental dietary cellulose reduces the incidence of colon cancer. Epidemiology studies also indicate that high dietary fiber reduces the risk of colorectal cancer in humans. Patients diagnosed with sporadic adenomas were entered into a randomized clinical trial to determine if supplemental dietary cellulose would reduce the patients' risk for colon cancer. Immunohistochemical staining for transforming growth factor alpha (TGF-alpha) was done on biopsies of rectal mucosa taken from patients at the time of initial polypectomy and 1 year later. Results were evaluated for utility as a surrogate end point biomarker for reduction in colon cancer risk. There was a significant decrease in the fraction of the rectal crypt cells that stained for TGF-alpha in six of seven of the patients given the cellulose supplements but in only one of six of the patients not given cellulose. Thus, whether evaluated as a group or in individual patients, there was a significant decrease in TGF-alpha in rectal crypts due to cellulose intervention, which correlated with the expected ability of supplemental dietary cellulose to decrease the risk for colon cancer. Long-term testing of the ability of dietary cellulose to reduce adenoma recurrence is under way to validate the use of TGF-alpha as a surrogate end point biomarker.

Endoscopic biliary stent migration with small bowel perforation in a liver transplant recipient.

Intestinal perforation from a migrated biliary stent is a rare complication after endoscopic stent placement for benign biliary stricture. We provide the first description of stent migration and distal small-bowel perforation after stent placement for biliary anastomotic stricture in a liver transplant recipient. We review the current literature on the diagnosis and management of stent migration and intestinal perforation after endoscopic or percutaneous stent placement for benign and malignant biliary strictures. Early diagnosis and treatment of biliary stent migration and subsequent intestinal perforation are essential in transplant patients, in whom immunosuppression sometimes blunts signs and symptoms of intestinal perforation.

Prevention and treatment of drug-induced liver disease.

Many drugs may cause liver damage; some damage is predictable, but most is not. The most important preventive measure is judicious drug use by the prescribing physician. Early recognition of hepatotoxicity and cessation of the offending agent is essential for treatment. The best example of a specific treatment for drug-induced liver disease is N-acetylcysteine treatment for acetaminophen hepatotoxicity. Many examples are cited of other attempts at treatment in animal models of drug-induced liver disease. If drug-induced liver disease leads to fulminant hepatic failure, intensive management of the resulting complications is required. Liver transplantation may be the only treatment option.

Effect of the nonimmunosuppressive cyclosporin analog SDZ PSC-833 on colchicine and doxorubicin biliary secretion by the rat in vivo.

Colchicine and doxorubicin are secreted into bile as a major pathway of their elimination. Colchicine and doxorubicin are also substrates for P-glycoprotein, and P-glycoprotein has been demonstrated to be present at the liver canalicular membrane. Cyclosporin (CsA) inhibits colchicine biliary secretion in vivo. In the present study, the effects of SDZ PSC-833, a nonimmunosuppressive cyclosporin D analog, on the biliary secretion of colchicine and doxorubicin were investigated. SDZ PSC-833 given at a bolus dose of 2 mg/kg promptly decreased colchicine biliary clearance from 9.05 +/- 0.2 to 2.41 +/- 0.43 ml min-1 kg-1 (P < 0.001) and the colchicine bile/plasma ratio from 146 +/- 8 to 35 +/- 5 (P < 0.001). SDZ PSC-833 also inhibited doxorubicin biliary clearance (basal: 10.5 +/- 3 vs post-SDZ PSC-833: 2.48 +/- 0.94 ml min-1 kg-1; P = 0.06) and the doxorubicin bile/plasma ratio (basal: 228 +/- 64 vs post-SDZ PSC-833: 48 +/- 22; P < 0.01). Colchicine renal secretion was completely inhibited by SDZ PSC-833. Thus, SDZ PSC-833 inhibits the constitutive transport of the multi-drug-resistance substrates colchicine and doxorubicin and is more potent than cyclosporin in this regard. The possibility of increased toxicity to normal tissues because of impaired elimination of cytotoxic agents will need to be considered if SDZ PSC-833 is used to chemosensitize cancer cells.

Effect of cyclosporine on colchicine partitioning in the rat liver.

Colchicine is secreted into bile as a major pathway of elimination. Cyclosporine (CsA) inhibits colchicine biliary secretion. In the present study, the effects of cyclosporine and its vehicle (cremophor) on the partitioning of colchicine across the liver were studied. CsA decreased the colchicine bile/plasma ratio from 484 +/- 39 to 53 +/- 3 (P < 0.001). This effect was due to both a decrease in bile/liver partitioning (control, 35.1 +/- 1.2, vs CsA treatment, 9.2 +/- 0.5; p < 0.001) as well as a decrease in liver/plasma partitioning (control, 13.7 +/- 0.8, vs CsA treatment, 5.7 +/- 0.4; P < 0.001). Cremophor also decreased the colchicine bile/plasma ratio (317 +/- 19, P < 0.02 vs control), but this effect was due to a decrease in the liver/plasma ratio (9.99 +/- 0.7, P < 0.02 vs control) rather than the bile/liver ratio (31.9 +/- 2.1, P > 0.2 vs control). Inhibition at the canalicular membrane is consistent with the location of gp-170, the presumed transporter of colchicine.

Uptake of the noncytotoxic transport probe procainamide in the Chinese hamster ovary model of multidrug resistance.

Many of the cytotoxic substrates of the multidrug transporter are organic cations. Cimetidine, procainamide, and tetraethylammonium bromide were used in a Chinese hamster ovary model of multidrug resistance, to study handling of noncytotoxic cationic transport probes. Cimetidine and procainamide, but not tetraethylammonium, accumulated to a greater extent (5-fold) in the sensitive CHOAUXB1 (AB) cell line than in the resistant CHRC5 (C5) cell line. Accumulation of both cimetidine and procainamide was significantly increased by verapamil in C5 but not AB. Procainamide accumulation in both AB and C5 was temperature dependent and occurred by passive diffusion. Diltiazem, nifedipine, rifampin, tamoxifen, rhodamine, and ethidium also increased procainamide accumulation in C5 but not AB. Azide in glucose-free medium increased procainamide accumulation in C5, and this was reversed when glucose, but not 3-O-methylglucose, was added. Procainamide efflux rates were similar in AB and C5 and not affected by verapamil or azide. The initial rate of procainamide uptake was higher in AB than in C5, and both verapamil and azide increased the initial rate of procainamide uptake in C5. Thus, differences in accumulation of the noncytotoxic transport probe procainamide in the colchicine-sensitive and colchicine-resistant components of the Chinese hamster ovary cell line mimic the accumulation of known cytotoxic substrates for the multidrug transporter, such as colchicine, vinblastine, and doxorubicin. The differential accumulation of procainamide is due to differences in rates of drug influx, rather than efflux. Since procainamide influx is passive and decreased accumulation in the resistant line appears to parallel M(r) 170,000 glycoprotein presence and activity, we would speculate that decreased procainamide accumulation may be due to an indirect effect of the M(r) 170,000 glycoprotein, such as its effect on intracellular pH.

Effect of cyclosporine on colchicine secretion by a liver canalicular transporter studied in vivo.

The multidrug resistance transport protein is a normal constituent of the liver canalicular membrane, although its function has not been defined in vivo. Colchicine, a multidrug resistance substrate, is eliminated mainly by the liver. Cyclosporine reverses multidrug resistance in vitro, presumably by inhibiting the multidrug resistance transporter. This study assesses biliary colchicine elimination and the effect of cyclosporine on this process. After cyclosporine administration biliary colchicine clearance decreased from 11.6 +/- 0.8 to 2.2 +/- 0.4 ml/min.kg (p less than 0.05), and the colchicine bile/plasma ratio decreased from 166 +/- 9 to 38 +/- 5 (p less than 0.05). Cremophor EL (a cyclosporine vehicle) transiently inhibited biliary colchicine clearance and colchicine bile/plasma ratio, but to a much smaller extent than cyclosporine in vehicle. Biliary cyclosporine clearance was 0.122 and 0.024 ml/min.kg after bolus doses of 2 or 10 mg/kg intravenously, respectively. Cyclosporine bile/plasma ratio was 1.3 to 5.2. When cyclosporine was given 16 hr before colchicine infusion, biliary colchicine clearance decreased 39% (p less than 0.05), and colchicine bile/plasma ratio decreased 51% (p less than 0.05). Thus colchicine is actively secreted into bile and will be useful in the study of the multidrug transporter in vivo. Cyclosporine profoundly inhibits colchicine secretion into bile but is itself mainly metabolized rather than secreted. If competition for a common carrier is the basis for the interaction, then cyclosporine represents a drug that binds to but is not transported by the canalicular transporter.

Effect of cyclosporine on colchicine secretion by the kidney multidrug transporter studied in vivo.

The multidrug resistance (MDR) transport protein is a normal constituent of proximal renal tubules although its function has not been defined in vivo. We find that colchicine, an MDR substrate, is secreted into urine by a process which is distinct from the organic cation transporter responsible for tetraethylammonium and N-methylnicotinamide secretion. Cyclosporine (CsA), which reverses MDR in vitro presumably by inhibiting the MDR transporter, inhibits colchicine renal secretion but does not inhibit the net secretion of the organic cation, ranitidine, or the organic anion, p-aminohippurate. After CsA (2 mg/kg i.v.), colchicine renal clearance decreased from 6.23 +/- 0.46 to 3.58 +/- 0.31 ml/min.kg (P less than .05), glomerular filtration rate was unchanged (4.21 +/- 0.08 and 3.88 +/- 0.17 ml/min.kg, before and after CsA, respectively; P = .09) and colchicine secretory ratio decreased from 1.48 +/- 0.11 to 0.92 +/- 0.07 (P less than .05). Cremophor (CsA vehicle) increased colchicine renal clearance (6.77 +/- 0.29 to 7.7 +/- 0.3 ml/min.kg, P less than .05) and colchicine secretory ratio (1.425 +/- 0.071 to 1.621 +/- 0.061, P less than .05). The inhibition of colchicine secretion was long-lived lasting at least 30 hr after CsA. Thus, colchicine is actively secreted into urine by the multidrug transporter in vivo. CsA profoundly inhibits colchicine secretion into urine while having no effect on the secretion of the organic cation ranitidine or the organic anion p-aminohippurate.

Colchicine clearance is impaired in alcoholic cirrhosis.

Colchicine may have benefit in primary biliary cirrhosis and alcoholic liver disease. It is currently used in patients with impaired liver function, yet little is known about its elimination in such patients. Colchicine clearance in the rat is significantly impaired in various models of liver disease. To study this in human beings, colchicine pharmacokinetics were compared in normal subjects and patients with alcoholic cirrhosis. Colchicine clearance was impaired in the cirrhotic patients. Normal subjects had a mean clearance of 10.65 +/- 1.82 ml/min.kg, whereas cirrhotic patients had a mean clearance of 4.22 +/- 0.45 ml/min.kg (p less than 0.01). The half-life was 57.4 +/- 14.2 min in control subjects vs. 114.4 +/- 19.7 min in cirrhotic patients (p = 0.054). Volume of distribution was not different in the two groups (0.718 +/- 0.1 L/kg in control subjects; 0.716 +/- 0.158 L/kg in cirrhotic patients, p greater than 0.99). No correlation was seen between colchicine clearance and bilirubin, albumin, prothrombin time or Child-Pugh classification, but this may be the result of the small number of patients studied. Based on the values measured, it is estimated that colchicine steady state would change from an average 1.12 ng/ml in normal individuals to 2.82 ng/ml in the cirrhotic patients if 0.6 mg were taken every 12 hr. It is unknown whether this change would be clinically significant. These data show that cirrhosis impairs colchicine clearance and demonstrates that the liver is a major route of colchicine elimination.

Isolation and characterization of an adriamycin-resistant breast tumor cell line.

An adriamycin-resistant human breast tumor cell line MDA-A1R was generated by step-wise selection in increasing concentrations of drug from the parent cell line MDA-MB-231. MDA-A1R cells grow as loosely attached cell aggregates with a doubling time of 28-32 h; the MDA-MB-231 parent cell line grows as a standard monolayer culture with a 20-h doubling time. The MDA-A1R cell line is highly resistant to adriamycin compared to the parent cell line, and is cross-resistant to velban and colchicine suggestive of a multidrug resistance (MDR) phenotype. MDA-A1R cells exhibit reduced net adriamycin content as compared to the parent cell line. The MDR-associated P-glycoprotein gene is amplified approximately 10- to 30-fold in MDA-A1R cells. P-glycoprotein sequences are overexpressed in the resistant cells and are stable for up to 13 wk after drug removal. Moreover, MDA-A1R cells show the presence of very high levels of P-glycoprotein. MDA-A1R is thus an in vitro model system to study the mechanism of MDR in human breast cancer.

The effect of liver dysfunction on colchicine pharmacokinetics in the rat.

Recent work has shown that colchicine may benefit patients with primary biliary or alcoholic cirrhosis. However, very little is known about its pharmacokinetics in the presence of impaired liver function. To study this we examined the effects of three models of experimental liver dysfunction and one of cytochrome P-450 inhibition on colchicine elimination in the rat. The models of experimental liver dysfunction included bile duct ligation (with sham-operated controls), alpha-naphthylisothiocyanate-induced intrahepatic cholestasis and galactosamine-induced diffuse hepatocellular necrosis. The control group had a colchicine clearance of 77.33 ml/min.kg +/- 8.27 ml/min.kg, a half-life of 16.68 min +/- 0.97 min and a volume of distribution of 1.84 L/kg +/- 0.15 L/kg. Cimetidine administration, 120 mg/kg intraperitoneally 15 min before colchicine administration, caused clearance to decrease by 32% (p less than 0.05) and half-life to increase by 38% (p less than 0.05). Volume of distribution did not change. At 48 hr after bile duct ligation, colchicine clearance decreased by 84% (p less than 0.05), terminal half-life increased to 513.7 min +/- 106.6 min (p less than 0.05) and volume of distribution increased by 175% (p less than 0.05). Colchicine pharmacokinetics in sham-operated rats were not statistically different from the above mentioned controls.(ABSTRACT TRUNCATED AT 250 WORDS)