Kwang Jong Lee

Induction of molecular chaperones in carbon tetrachloride–treated rat liver: implications in protection against liver damage

Abstract Carbon tetrachloride (CCl4) induces liver damage, apparently through the formation of free-radical metabolites. Molecular chaperones such as heat shock protein (Hsp) of 70 kDa have been found to protect cells from various stresses. We previously found that cytosolic chaperone pairs of the Hsp70 family and their DnaJ homolog cochaperones prevent nitric oxide–mediated apoptosis and heat-induced cell death. Expression of cytosolic chaperones, including Hsp70; heat shock cognate (Hsc) 70; and DnaJ homologs dj1 (DjB1/Hsp40/hdj-1), dj2 (DjA1/HSDJ/hdj-2), dj3 (DjA2), and dj4 (DjA4), in the liver of CCl4-treated rats was analyzed. Messenger ribonucleic acids for all these chaperones were markedly induced 3–12 hours after CCl4 treatment with a maximum at 6 hours. Hsp70 and dj1 proteins were markedly induced at 6–24 hours with a maximum at 12 hours, whereas dj2 and dj4 were moderately induced at around 12 hours. Hsc70 was weakly induced after treatment, and dj3 was little induced. To better understand the significance of the induction of chaperones, the effect of preinduction of chaperones on CCl4-induced liver damage was analyzed. When chaperones were preinduced in the liver by heat treatment, increase in serum alanine aminotransferase activity after CCl4 treatment was significantly attenuated. Hsp90, another major cytosolic chaperone, also was induced by heat treatment. On the other hand, Mn- and Cu/Zn-superoxide dismutase were not induced by heat treatment or by CCl4 treatment. These results suggest that cytosolic chaperones of Hsp70 and DnaJ families or Hsp90 (or both) are induced in CCl4-treated rat liver to protect the hepatocytes from the damage being inflicted.

Incidence and risk factors for new-onset diabetes in living-donor liver transplant recipients.

With the increased number of long‐term survivors after liver transplantation, new‐onset diabetes after transplantation (NODAT) is becoming more significant in patient follow‐up. However, the incidence of new‐onset diabetes after living‐donor liver transplantation (LDLT) has not been well elucidated. The aim of this study was to evaluate the incidence and risk factors for NODAT in adult LDLT recipients at a single center in Japan. A retrospective study was performed on 161 adult patients without diabetes who had been followed up for ≥three months after LDLT. NODAT was defined according to the 2003 American Diabetes Association/World Health Organization guidelines. The recipient‐, donor‐, operation‐, and immunosuppression‐associated risk factors for NODAT were assessed. Overall, the incidence of NODAT was 13.7% (22/161) with a mean follow‐up of 49.8 months. In a multivariate analysis, the identified risk factors for NODAT were donor liver‐to‐spleen (L‐S) ratio (hazard ratio [HR] = 0.022, 95% confidence interval [CI] = 0.001–0.500, p = 0.017), and steroid pulse therapy for acute rejection (HR = 3.320, 95% CI = 1.365–8.075, p = 0.008). In conclusion, donor L‐S ratio and steroid pulse therapy for acute rejection were independent predictors for NODAT in LDLT recipients. These findings can help in screening for NODAT and applying early interventions.

Management of undifferentiated sarcoma of the liver including living donor liver transplantation as a backup procedure

We present the cases of 3 children with huge undifferentiated sarcoma of the liver who were treated with surgical excision including liver transplantation as an option and adjuvant chemotherapy. All 3 patients were males aged 10, 13, and 15 years old. The size of the tumor was 10, 15, and 20 cm in diameter, respectively. The youngest patient is disease free and doing well 43 months after resection. The 13-year-old patient presented with tumor rupture and underwent operation. The primary tumor and the ruptured tissue fragments were removed and he was given postoperative chemotherapy. The patient is disease free and doing well 52 months after surgery. The oldest patient had an unresectable tumor in the hilar region. Preoperative chemotherapy was given but later discontinued owing to severe side effects. He underwent living donor liver transplantation followed by postoperative chemotherapy. The patient had recurrent tumor 24 months after transplantation that was excised at reoperation. He is doing well and is disease free 18 months after the second procedure. Complete removal of the tumor including total hepatectomy and transplantation when indicated and suitable pre- and/or postoperative chemotherapy is an effective treatment for children with undifferentiated sarcoma of the liver.

Coefficient factor for graft weight estimation from preoperative computed tomography volumetry in living donor liver transplantation

In the clinical setting of living donor liver transplantation (LDLT), it is common to find a discrepancy between the graft volume estimated by preoperative computed tomography volumetry and the actual graft weight (AGW) measured on the back‐table. In this study, we attempt to find the coefficient factor that correlates the estimated graft volume to the AGW. Whole livers explanted in 25 LDLT recipients (17 cirrhotic and 8 morphologically normal with familial amyloid polyneuropathy) were evaluated to compare cirrhotic livers and noncirrhotic normal livers. In addition, right lobe grafts (n = 39) and left lobe grafts (n = 35) used in LDLTs were also evaluated to further determine the correlation between estimated graft volume and AGW. The correlation coefficient between estimated liver volume and actual liver weight was 1.01 in whole cirrhotic livers, whereas it was 0.85 in whole livers with familial amyloid polyneuropathy. In the partial liver grafts, it was 0.84 in right lobe grafts and 0.85 in left lobe grafts. In conclusion, we suggest that a correlation coefficient of 0.85 should be applied for the accurate calculation of the graft weight from the volume estimated by preoperative computed tomography in LDLT. Liver Transpl, 2011.

How to handle a huge portosystemic shunt in adult living donor liver transplantation with a small-for-size graft: report of a case.

Little attention has been paid to a ligation of the spontaneous portosystemic shunt in adult living donor liver transplantation (LDLT). A 33-year-old Japanese man with cryptogenic liver cirrhosis accompanied by a huge splenorenal shunt underwent LDLT. Acute cellular rejection produced “to and fro” portal venous flow on postoperative day (POD) 10. Steroid bolus therapy reversed the rejection, but the recovery of the portal venous flow was incomplete and the recipient subsequently started to have episodes of encephalopathy. Angiography showed portal hypoperfusion and portal flow steal via a huge splenorenal shunt. The patient underwent a shunt occlusion on POD 58. Portography showed marked improvement of the portal hypoperfusion. The encephalopathy thereafter dramatically reversed and the patient was discharged with no complications related to shunt ligation on POD 110. This case suggested that a ligation of a huge portosystemic shunt should therefore be considered at the time of transplantation, even when a relatively small graft is implanted.

Living donor liver transplantation from a heterozygous parent for classical maple syrup urine disease

MSUD is a hereditary metabolic disorder that is characterized by impaired activity of the BCKADC. Liver transplantation has been approved as a treatment for some MSUD cases in which the control of BCAAs is insufficient. Although there have been several reports about DDLT for MSUD, few LDLT cases have been reported. Because either of parents who are heterozygote of this disease usually applies to be a candidate of donor in LDLT, the impairment of BCKADC activity of graft liver should be concerned. We performed LDLT for 10 month‐old girl with a left lateral segment graft from her father. BCKADC activities of the patient and her parents were measured using lysates of lymphocytes isolated from peripheral blood specimen before the transplant. As a consequence, the activity of BCKADC of father was not inferior to a normal range. The patient tolerated the operation well. Postoperative course was uneventful and mixed milk was started at 8th POD. The serum BCAAs levels have remained within normal range. It should be necessary to follow the physical growth and mental development of the recipient in the future.

Re-evaluation of the indications for liver transplantation in Wilson's disease based on the outcomes of patients referred to a transplant center.

The aim of this study was to re‐evaluate the indications and timing of LT for WD. From 2000 to 2009, eight patients with WD who had been referred to our institution for LT were enrolled in this study. The mean patient age was 15.9 yr (range, 7–37 yr). Four patients could not receive LT, because there were no available donors. All four patients were treated with chelating agent medication. Three of them (two of two patients with fulminant WD and one of two with cirrhotic WD) who did not undergo LT are still alive and doing well with stable liver functional tests. Only one of the patients with cirrhotic WD who did not undergo LT died of hepatic failure. Even among the four patients who underwent LT, one with fulminant WD recovered from hepatic encephalopathy with apheresis therapy and chelating agent. He later required LT because of severe neutropenia from d‐penicillamine. The other three patients who underwent LT recovered and have been doing well. Some of the patients with WD can recover and avoid LT with medical treatment. Even when WD has progressed liver cirrhosis and/or fulminant hepatic failure at the time of diagnosis, medical treatment should be tried before considering LT.

The Skt gene, required for anorectal development, is a candidate for a molecular marker of the cloacal plate

Background and aimsIt has been reported that a dorsal cloacal plate defect is associated with anorectal malformations (ARMs); however, there has been very little information reported about the developmental mechanisms involved with cloacal plate formation. Danforth’s short tail (Sd) mutant mice show ARMs. In our previous study, the co-presence of SktGt mutation, in which Skt gene is disrupted by the gene-trap vector (p-U8), increased the incidence of ARMs in Sd mutant to 100%. Our aims in this study are determining the Skt expression around the cloaca during the anorectal development and demonstrating the role of Skt gene in ARMs.MethodsEmbryos, normal controls [+SktGt/+SktGt] and ARMs models [Sd SktGt/+SktGt], from embryonic day (E) 9.5 to E12.5, were evaluated with X-gal staining.ResultsIn control embryos, Skt expression was detected both in the endoderm and ectoderm of the cloacal plate from E9.5 onward. At E12.5, Skt expression was also detected in the mesenchyme neighboring the dorsal cloacal plates. In [Sd SktGt/+SktGt] mutant embryos, the cloacal plates failed to extend proximodistally and, consequently, the dorsal part of cloacal plate was defective at E11.5. Skt expressing cells were detected in the shortened cloacal plate and in the thickened mesenchyme dorsal to it.ConclusionsWe showed the spatial and temporal expression of Skt gene in the cloacal plate formation. This gene could be a marker for the cloacal plate during the anorectal development. Furthermore, Skt was considered to be associated with the embryogenesis of ARMs.

Current state of domino transplantation in Japan in terms of surgical procedures and de novo amyloid neuropathy

The status of domino liver transplantation (DLT) in Japan was evaluated. DLT and familial amyloidotic polyneuropathy (FAP) recipients who underwent living donor liver transplantation (LDLT) at Kumamoto University were reviewed with attention to surgical procedures. Thirty-nine DLTs were performed in Japan until 2010, and survival rates at 1 and 3 years were 82% and 63.6%, respectively. Six of 21 DLT recipients who survived for more than 3 years developed amyloid depositions within organs, and de novo amyloid neuropathy was reported in three patients. DLT from FAP recipients in Kumamoto was safely performed with preservation of the retrohepatic inferior vena cava in FAP recipients. All 20 FAP recipients who were DLT donors are alive with the exception of one who died of the original FAP 9 years after LDLT. The outcomes of DLT and FAP recipients in Kumamoto were satisfactory.

Single-center experience and long-term outcomes of duct-to-duct biliary reconstruction in infantile living donor liver transplantation

The indications for duct‐to‐duct (DD) biliary reconstruction in living donor liver transplantation (LDLT) for small children are still controversial. In this study, the feasibility of DD biliary reconstruction versus Roux‐en‐Y (RY) biliary reconstruction was investigated in terms of long‐term outcomes. Fifty‐six children who consecutively underwent LDLT with a weight less than or equal to 10.0 kg were enrolled. Biliary reconstruction was performed in a DD fashion for 20 patients and in an RY fashion for 36 patients. During a minimum follow‐up of 2 years, the incidence of biliary strictures was 5.0% in the DD group and 11.1% in the RY group. Cholangitis during the posttransplant period was observed in the RY group only. There were no deaths related to biliary problems. This study shows that DD reconstruction in LDLT for small children (weighing 10.0 kg or less) is a feasible option for biliary reconstruction. Liver Transpl 20:347‐354, 2014.