John P. Roberts

Recurrent and acquired hepatitis C viral infection in liver transplant recipients

To examine the postliver transplant recurrence of hepatitis C virus (HCV) infection in patients with pretransplant infection, as well as its acquisition in patients without prior infection, we used the polymerase chain reaction to amplify HCV RNA in serum and/or liver samples of 89 patients with alcoholic and cryptogenic cirrhosis undergoing liver transplantation. Results were correlated with histologic findings from posttransplant liver biopsies. Ninety-five percent of patients with pretransplant infection had posttransplant viremia. In contrast, 35% of patients without pretransplant infection acquired the virus (P less than 0.0001). Pretransplant HCV infection predisposed patients to hepatitis in the new graft. HCV RNA was present in serum of 96% of patients with posttransplant hepatitis. Fifty-six percent of patients with posttransplant HCV infection had no evidence of liver damage at least 1 year posttransplant. However, of those patients with histologic hepatitis, chronic active hepatitis was common. It is concluded that although HCV infection recurs posttransplant in almost all infected patients, acquisition of the HCV infection with transplant is common. Pretransplant HCV infection is an independent risk factor for the development of posttransplant hepatitis. HCV infection accounts for the majority of posttransplant hepatitis not due to cytomegalovirus, and although many patients with posttransplant viremia have little evidence of histologic hepatitis, significant hepatic damage may occur.

Bargaining and Influence Costs and the Organization of Economic Activity

This chapter is concerned with the economics of organization and management, a relatively new area of study that seeks to analyze the internal structure and workings of economic organizations, the division of activity among these organizations, and the management of relations between them through markets or other higher-level, encompassing organizations. The dominant approach to this subject is transaction-cost economics, as introduced by Coase (1937, 1960) and developed by several others since, most notably Williamson (1975, 1985). The main tenet of Coases theory is that economic activities tend to be organized efficiently – that is, so as to maximize the expected total wealth of the parties affected. In this context, two sorts of costs are customarily identified – those of physical production and distribution and those of carrying out necessary exchanges. Because these are typically treated as distinct and separable, the efficiency hypothesis becomes one of transaction-cost minimization: The division of activities among firms and between a firm and the market is determined by whether a particular transaction is most efficiently conducted in a market setting or under centralized authority within a firm. This approach has two conceptual problems. First, the total costs a firm incurs cannot generally be expressed as the sum of production costs – depending only on the technology and the inputs used – and transaction costs – depending only on the way transactions are organized. In general, these two kinds of costs must be considered together; efficient organization is not simply a matter of minimizing transaction costs.

Excellent Outcome Following Down-Staging of Hepatocellular Carcinoma Prior to Liver Transplantation: An Intention-to-Treat Analysis

We previously reported encouraging results of down‐staging of hepatocellular carcinoma (HCC) to meet conventional T2 criteria (one lesion 2–5 cm or two to three lesions <3 cm) for orthotopic liver transplantation (OLT) in 30 patients as a test of concept. In this ongoing prospective study, we analyzed longer‐term outcome data on HCC down‐staging in a larger cohort of 61 patients with tumor stage exceeding T2 criteria who were enrolled between June 2002 and January 2007. Eligibility criteria for down‐staging included: (1) one lesion >5 cm and up to 8 cm; (2) two to three lesions with at least one lesion >3 cm and not exceeding 5 cm, with total tumor diameter up to 8 cm; or (3) four to five lesions with none >3 cm, with total tumor diameter up to 8 cm. A minimum observation period of 3 months after down‐staging was required before OLT. Tumor down‐staging was successful in 43 patients (70.5%). Thirty‐five patients (57.4%) had received OLT, including two who had undergone live‐donor liver transplantation. Treatment failure was observed in 18 patients (29.5%), primarily due to tumor progression. In the explant of 35 patients who underwent OLT, 13 had complete tumor necrosis, 17 met T2 criteria, and five exceeded T2 criteria. The Kaplan‐Meier intention‐to‐treat survival at 1 and 4 years after down‐staging were 87.5% and 69.3%, respectively. The 1‐year and 4‐year posttransplantation survival rates were 96.2% and 92.1%, respectively. No patient had HCC recurrence after a median posttransplantation follow‐up of 25 months. The only factor predicting treatment failure was pretreatment alpha‐fetoprotein >1,000 ng/mL. Conclusion: Successful down‐staging of HCC can be achieved in the majority of carefully selected patients and is associated with excellent posttransplantation outcome. (HEPATOLOGY 2008.)

Bioavailability of cyclosporine with concomitant rifampin administration is markedly less than predicted by hepatic enzyme induction.

The pharmacokinetics of cyclosporine was studied in six healthy volunteers after administration of the drug orally (10 mg/kg) and intravenously (3 mg/kg) with and without concomitant rifampin administration. Both blood and plasma (separated at 37° C) samples were analyzed for cyclosporine concentration. For blood and plasma, respectively, clearances of cyclosporine were calculated to be 0.30 and 0.55 L/hr/kg, values for volume of distribution at steady state were 1.31 and 1.68 L/kg, and bioavailabilities were 27% and 33% during the pre‐rifampin phase. Post‐rifampin phase clearances of cyclosporine were 0.42 and 0.79 L/hr/kg, values for volume of distribution at steady state were 1.36 and 1.35 L/kg, and bioavailabilities were 10% and 9% for blood and plasma, respectively. Rifampin not only induces the hepatic metabolism of cyclosporine but also decreases its bioavailability to a greater extent than would be predicted by the increased metabolism. The decreased bioavailability most probably can be explained by an induction of intestinal cytochrome P450 enzymes, which appears to be markedly greater than the induction of hepatic metabolism.

Liver Transplantation for Hepatocellular Carcinoma: Validation of the UCSF‐Expanded Criteria Based on Preoperative Imaging

We previously suggested that in patients with heptocellular carcinoma (HCC), the conventional Milan criteria (T1/T2) for orthotopic liver transplantation (OLT) could be modestly expanded based on pathology (UCSF criteria). The present study was undertaken to prospectively validate the UCSF criteria based on pretransplant imaging. Over a 5‐year period, the UCSF criteria were used as selection guidelines for OLT in 168 patients, including 38 patients exceeding Milan but meeting UCSF criteria (T3A). The 1‐ and 5‐year recurrence‐free probabilities were 95.9% and 90.9%, and the respective survivals without recurrence were 92.1% and 80.7%. Patients with preoperative T1/T2 HCC had 1‐ and 5‐year recurrence‐free probabilities of 95.7% and 90.1%, respectively, versus 96.9% and 93.6%, respectively, for preoperative T3A stage (p = 0.58). Under‐staging was observed in 20% of T2 and 29% of T3A HCC (p = 0.26). When explant tumor exceeded UCSF criteria (15%), the 1‐ and 5‐year recurrence‐free probabilities were 80.4% and 59.5%, versus 98.6% and 96.7%, respectively, for those within UCSF criteria (p < 0.0001). In conclusion, our results validated the ability of the UCSF criteria to discriminate prognosis after OLT and to serve as selection criteria for OLT, with a similar risk of tumor recurrence and under‐staging when compared to the Milan criteria.

The risk of transmission of hepatitis B from HBsAg(-), HBcAb(+), HBIgM(-) organ donors.

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.

Functional analysis of grafts from living donors. Implications for the treatment of older 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.

Adaptive and sophisticated learning in normal form games

Abstract In a class of games including some Cournot and Bertrand games, a sequence of plays converges to the unique Nash equilibrium if and only if the sequence is “consistent with adaptive learning” according to the new definition we propose. In the Arrow-Debreu model with gross substitutes, a sequence of prices converges to the competitive equilibrium if and only if the sequence is consistent with adaptive learning by price-setting market makers for the individual goods. Similar results are obtained for “sophisticated” learning. All the familiar learning algorithms generate play that is consistent with adaptive learning. Journal of Economic Literature Classification Numbers: 026, 021.

Serum sodium predicts mortality in patients listed for liver transplantation.

With the implementation of the model for end‐stage liver disease (MELD), refractory ascites, a known predictor of mortality in cirrhosis, was removed as a criterion for liver allocation. Because ascites is associated with low serum sodium, we evaluated serum sodium as an independent predictor of mortality in patients with cirrhosis who were listed for liver transplantation and whether the addition of serum sodium to MELD was superior to MELD alone. This is a single‐center retrospective cohort of all adult patients with cirrhosis listed for transplantation from February 27, 2002, to December 26, 2003. Listing laboratories were those nearest the listing date ±2 months. Of the 513 patients meeting inclusion criteria, 341 were still listed, while 172 were removed from the list (105 for transplantation, 56 for death, 11 for other reasons). The median serum sodium and MELD scores were 137 mEq/L (range, 110‐155) and 15 (range, 6‐51), respectively, at listing. Median follow‐up was 201 (range, 1‐662) days. The risk of death with serum sodium < 126 mEq/L at listing or while listed was increased, with hazard ratios of 7.8 (P < .001) and 6.3 (P < .001), respectively, and the association was independent of MELD. The c‐statistics of receiver operating characteristic curves for predicting mortality at 3 months based upon listing MELD with and without listing serum sodium were 0.883 and 0.897, respectively, and at 6 months were 0.871 and 0.905, respectively. In conclusion, serum sodium < 126 mEq/L at listing or while listed for transplantation is a strong independent predictor of mortality. Addition of serum sodium to MELD increases the ability to predict 3‐ and 6‐month mortality in patients with cirrhosis. (HEPATOLOGY 2005;41:32–39.)

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.