Federico G. Villamil

Liver transplantation (OLT) is indicated in patients with severe and irreversible acute or chronic liver disease without alternative therapy and in the absence of contraindications. Indications for OLT can be grouped in four categories, namely cirrhosis, fulminant hepatitis, malignant hepatic tumors and liver-based genetic defects that trigger damage of other organs. Patients with cirrhosis should be referred for OLT after the onset of any of the major complications or coagulopathy. Early referral is crucial in fulminant hepatitis due to the high mortality with medical therapy and the unpredictable nature of this condition. Ideal timing for OLT is the moment in the natural history of the disease when the expected survival of patients on the waiting list is higher with than without OLT. Recent data suggest that maximal benefit of OLT is obtained in patients with a MELD score >15. However, in some cases with no imminent risk of death, OLT is indicated to improve quality of life or to prevent contraindications such as progression of hepatocellular carcinoma. At present, there is a marked disproportion between the number of donors available and the growing number of patients listed worldwide, which in turn has resulted in prolongation of the time-interval to OLT and waitlist mortality. The rationale of allocation systems utilizing the MELD score is to prioritize on the waiting list patients with severe liver dysfunction ("the sickest first") and those with hepatocellular carcinoma who may loose the benefits of OLT when waitlist time exceeds eight months.

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Assessment of prognosis in fulminant hepatic failure (FHF) is essential for the need and appropriate timing of orthotopic liver transplantation (OLT). In this study we investigated the prognostic efficacy of King's College criteria, Clichy's criteria, Model for End-Stage Liver Disease (MELD), and Pediatric End-Stage Liver Disease (PELD) in 120 consecutive patients with FHF. Survival with medical therapy (18%), death without OLT (15%), and receipt of a liver transplant were similar in adults (n = 64) and children (n = 56). MELD scores were significantly higher in patients who died compared to those who survived without OLT, both in adults (38 ± 7 vs. 26 ± 7, P = 0.0003) and children (39 ± 7 vs. 23 ± 6, P = 0.0004). Using logistic regression analysis in this cohort of patients, concordance statistics were significantly higher for MELD (0.95) and PELD (0.99) when compared to King's College (0.74) and Clichy's criteria (0.68). When data was analyzed in a Cox model including patients receiving transplants and censoring the time from admission, the concordance statistic for MELD (0.77) and PELD (0.79) remained significantly higher than that of King's College criteria but not higher than that of Clichy's criteria. In conclusion, this study is the first to show that MELD and PELD are superior to King's College and Clichy's criteria to assess prognosis in FHF. However, because data was generated from a single center and included a rather low number of patients who survived or died without OLT, further confirmation of our findings is required. Liver Transpl 13:822–828, 2007. © 2007 AASLD.

The mean time to peak absorption of cyclosporine (CsA) in liver transplant patients is approximately 2 hours, but in some patients the peak occurs later. The goal of this study was, therefore, to investigate the incidence of delayed absorption in 27 de novo liver transplant recipients receiving CsA ≥10 mg/kg/day (C2 monitoring) and in 15 maintenance patients. Patients were categorized as ‘normal’ absorbers (C2 exceeding C4 and C6) or ‘delayed’ absorbers (C4 or C6 exceeding C2), and as ‘good’ (>800 ng/mL at C0, C2, C4, or C6) or ‘poor’ absorbers (C0, C2, C4 and C6 de novo patients, 15 (56%) had ‘normal’ CsA absorption and 12 (44%) ‘delayed’ absorption. Good CsA absorption occurred in 16 patients (59%) and poor absorption in 11 (41%). The proportion of poor absorbers was similar in patients with normal (6 / 15, 40%) or delayed (5 / 12, 42%) absorption. Among the 12 delayed absorbers, 11 had peak CsA concentration at C4. Mean C0 level was significantly higher in delayed absorbers (282 ± 96 ng/mL) than in normal absorbers (185 ± 88ng/mL; P = .01). Delayed absorbers reverted to normal absorption (C2 > C4) after a median of 6 days from the day of study, and no cases of delayed absorption were found among maintenance patients. In conclusion, almost 50% of the patients had delayed CsA absorption early posttransplant; around half of these exhibited normal CsA exposure. Measurement of C4 in addition to C2 differentiates effectively between delayed and poor absorbers of CsA such that over- or underimmunosuppression can be avoided. (Liver Transpl 2005;11:167–173.)

Adjusting cyclosporine (CsA) dose based on blood concentration at 2 hours after dose (C₂) has been shown in prospective clinical trials to reduce the risk of rejection compared with conventional trough monitoring. In addition, it provides equivalent efficacy to tacrolimus in liver transplant patients, with a favorable safety profile. Target C₂ should be defined on an individual basis depending on adjunctive therapy and the level of exposure required. It appears less critical to achieve target C₂ in the first few days after liver transplantation than was previously believed. Achieving target C₂ exposure in the initial period after transplant requires that changes in the proportion of cyclosporine absorbed from the gut be taken into account to avoid risk of overexposure. In addition, if a starting dose of 10-15 mg/day is used, it is advisable to delay increasing the dose until a trend in C₂ level indicates this to be necessary. Immediate dose reduction is required if C₂ exceeds target range. In patients with low C₂ values, cyclosporine concentration at a later time point should be measured to establish whether the patient is a poor absorber or a delayed absorber of C₂, and dose adjustments should be undertaken accordingly. In conclusion, this more flexible approach to C₂ monitoring allows the dose of cyclosporine to be individualized effectively for each patient, which results in significant efficacy benefits while minimizing the risk of toxicity. (Liver Transpl 2004;10:577-583.)

1. Patients undergoing orthotopic liver transplantation (OLT) for hepatitis B without effective prophylaxis have a high risk for recurrent infection and severe graft damage, leading to death or re-OLT. 2. Long-term prophylaxis with hepatitis B immune globulin (HBIg) significantly reduces the risk for hepatitis B virus (HBV) recurrence and increases survival. Patients with detectable HBV DNA at the time of OLT have a high risk for recurrence despite HBIg prophylaxis. 3. Lamivudine (LAM) therapy for patients with decompensated HBV cirrhosis before OLT results in inhibition of viral replication and clinical improvement. Its efficacy is limited by the frequent emergence of LAM-resistant YMDD mutations. The ideal length of therapy with LAM pre-OLT has not yet been defined. 4. Prophylaxis of HBV recurrence with LAM monotherapy is not recommended because of the reappearance of hepatitis B surface antigen after OLT in approximately 50% of patients. 5. LAM is the best available treatment for patients with established recurrent hepatitis B. Long-term therapy is associated with the emergence of drug-resistant mutants in up to 60% of patients. Severe hepatitis and liver failure have been described among liver transplant recipients with YMDD mutations. 6. Combination therapy with HBIg and LAM prevents HBV recurrence in 90% to 100% of patients who undergo OLT for hepatitis B. The optimal HBIg protocol in the LAM era is yet to be defined. 7. Preliminary studies suggest that adefovir dipivoxil inhibits HBV replication in patients infected with LAM-resistant HBV strains. 8. Fifteen years ago, hepatitis B was regarded as a relative or absolute contraindication for OLT. Today, hepatitis B is a universally accepted indication for OLT.