Hyang Sook Kim

Impact of immunosuppressant therapy on early recurrence of hepatocellular carcinoma after liver transplantation

Background/Aims The most commonly used immunosuppressant therapy after liver transplantation (LT) is a combination of tacrolimus and steroid. Basiliximab induction has recently been introduced; however, the most appropriate immunosuppression for hepatocellular carcinoma (HCC) patients after LT is still debated. Methods Ninety-three LT recipients with HCC who took tacrolimus and steroids as major immunosuppressants were included. Induction with basiliximab was implemented in 43 patients (46.2%). Mycophenolate mofetil (MMF) was added to reduce the tacrolimus dosage (n=28, 30.1%). The 1-year tacrolimus exposure level was 7.2 ± 1.3 ng/mL (mean ± SD). Results The 1- and 3-year recurrence rates of HCC were 12.9% and 19.4%, respectively. Tacrolimus exposure, cumulative steroid dosages, and MMF dosages had no impact on HCC recurrence. Induction therapy with basiliximab, high alpha fetoprotein (AFP; >400 ng/mL) and protein induced by vitamin K absence/antagonist-II (PIVKA-II; >100 mAU/mL) levels, and microvascular invasion were significant risk factors for 1-year recurrence (P<0.05). High AFP and PIVKA-II levels, and positive 18fluoro-2-deoxy-d-glucose positron-emission tomography findings were significantly associated with 3-year recurrence (P<0.05). Conclusions Induction therapy with basiliximab, a strong immunosuppressant, may have a negative impact with respect to early HCC recurrence (i.e., within 1 year) in high-risk patients.

Tacrolimus therapy causes hepatotoxicity in patients with a history of liver disease.

OBJECTIVE Tacrolimus is known to have little hepatotoxicity. Nevertheless, a few case studies have shown liver toxicities of tacrolimus, particularly in patients on multiple medications. This study is a retrospective data analysis on the potential of tacrolimus hepatotoxicity. METHODS A data analysis was conducted on the electronic medical records (EMRs) of 2,462 Korean patients taking tacrolimus or cyclosporine from 2002 through to 2008. Alanine aminotransferase (ALT) and total bilirubin level (TBL) were also monitored. The maximum ALT, time to reach ALTmax (TALTmax), and TBL(ALTmax) were compared between the tacrolimus and cyclosporine groups. Other possible factors that may aggravate liver function were also investigated. RESULTS ALTmax and TBL(ALTmax) were higher in the tacrolimus group compared to the cyclosporine group (i.e., 50 IU/L vs. 41 IU/L and 1 mg/dL vs. 0.9 mg/dL, respectively), and TALTmax was shorter (i.e., 101 days vs. 142 days) in the tacrolimus group. In addition, the frequency of ALTmax > 3x upper limit of normal (ULN) (i.e., ALTmax > 120) was significantly increased in the tacrolimus group compared to the cyclosporine group (30% vs. 21%). The severity of tacrolimusinduced liver damage was greater in patients with history of liver disease, as indicated by > two-fold greater ALTmax than that of cyclosporine (i.e., 153 IU/L vs. 65 IU/L). Moreover, the ALTmax was significantly lowered by switching from tacrolimus to cyclosporine in patients with a history of liver disease. In patients with preexisting renal disease, neither tacrolimus nor cyclosporine showed any effect on ALTmax. CONCLUSION Results indicate that tacrolimus may have a higher risk of inducing liver injury in Korean patients with a history of liver disease and may require close monitoring.

Higher plasma bilirubin predicts veno-occlusive disease in early childhood undergoing hematopoietic stem cell transplantation with cyclosporine

AIM To analyze the association between plasma bilirubin levels and veno-occlusive disease (VOD) in non-adult patients undergoing hematopoietic stem cell transplantation (HSCT) during cyclosporine therapy. METHODS A total of 123 patients taking cyclosporine were evaluated using an electronic medical system at the Seoul National University Childrens Hospital from the years 2004 through 2011. Patients were grouped by age and analyzed for incidence and type of adverse drug reactions (ADRs) including VOD. RESULTS The HSCT patients were divided into three age groups: G#1 ≥ 18; 9 ≤ G#2 ≤ 17; and G#3 ≤ 8 years of age). The majority of transplant donor types were cord blood transplantations. Most prevalent ADRs represented acute graft-vs-host disease (aGVHD) and VOD. Although the incidences of aGVHD did not vary among the groups, the higher frequency ratios of VOD in G#3 suggested that an age of 8 or younger is a risk factor for developing VOD in HSCT patients. After cyclosporine therapy, the trough plasma concentrations of cyclosporine were lower in G#3 than in G#1, indicative of its increased clearance. Moreover, in G#3 only, a maximal total bilirubin level (BILmax) of ≥ 1.4 mg/dL correlated with VOD incidence after cyclosporine therapy. CONCLUSION HSCT patients 8 years of age or younger are more at risk for developing VOD, diagnosed as hyperbilirubinemia, tender hepatomegaly, and ascites/weight gain after cyclosporine therapy, which may be represented by a criterion of plasma BILmax being ≥ 1.4 mg/dL, suggestive of more sensitive VOD indication in this age group.