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The liver is the major organ for the metabolism of homocysteine (Hcy) and production of insulin-like growth factor 1 (IGF-1). Hcy metabolism and IGF-1 synthesis may be impaired in chronic liver diseases. The study investigated the regulatory effect of a Chinese herbal suppository, Vitalliver, on Hcy and IGF-1, as well as their relationship in patients with hepatitis B infection. Forty patients with chronic hepatitis B virus (HBV) infection without cirrhosis, 25 males and 15 females, were observed for changes in Hcy and IGF-1 after the administration of Vitalliver (one nightly) for a period of 3 months. Serum levels of Hcy, IGF-1 and IGFBP-3 were measured at baseline, and at 1 month and 3 months after treatment. Vitalliver reduced Hcy levels significantly (p = 0.001) from 9.7 +/- 2.8 to 9.0 +/- 2.1 micromol/L after treatment of 3 months. Furthermore, the IGF-1 levels increased significantly (p < 0.001) from 170.2 +/- 81.8 to 212.8 +/- 80.9 ng/mL at 1 month and 187.5 +/- 72.3 ng/mL at 3 months (p = 0.001) after treatment. In conclusion, it is speculated Vitalliver may have a self-regulatory effect on the release of IGF-1 in HBV patients without liver cirrhosis.

p53 has recently been identified as a downstream target of ZBP-89, a zinc finger transcription factor. ZBP-89 promotes growth arrest through stabilization of the p53 protein. The aim of this study is to determine the status of the p53 gene in recurrent human hepatocellular carcinoma (HCC) and test the link between the expression of ZBP-89 and the p53 gene. The results showed that mutations in the p53 gene were frequently detected in recurrent HCC. The interval between surgical resection and the recurrence of HCC was significantly longer in patients with the wild-type p53 gene than those with mutations, strongly suggesting a pathological role for the mutant p53 gene in HCC recurrence. Among those positive for the p53 protein, nearly 85% (18 of 21) showed nuclear localization of the p53 protein while only about 14% (3 of 21) were positive for the p53 protein in the cytoplasm. ZBP-89 co-localized with p53 in the nucleus in about 67% (12 of 18) of all cases positive for the nuclear p53 protein, suggesting that ZBP-89 may play a role in the nuclear accumulation of the p53 protein in a subset of recurrent HCC. With accumulation of p53 protein in the nucleus, tumor cells undergo apoptosis and thus are more susceptible to radiotherapy and chemotherapy. Therefore, co-localization of p53 protein with ZBP-89 may define a subgroup of recurrent HCC that is more sensitive to treatment.

Bismuth type IV hilar cholangiocarcinoma (CC) carries a poor prognosis; however, ex vivo liver resection and autotransplantation (Atx) is theoretically a treatment option. There are only five previously reported cases of this procedure for hilar CC in the English literature, and most of them died early in the postoperative period. The only reported survivor died of tumor recurrence at 13 months. We are reporting a patient who has survived for 17 months without any sign of tumor recurrence. This probably represents the world's first cure for CC using this technique. This patient is a 26-year-old woman with a Bismuth Type IV CC. Portal vein involvement at the confluence was shown on angiogram, and in situ resection was deemed impossible. Ex vivo resection of segments five, six, seven, eight, and part of segment four was performed followed by a partial liver Atx. The pathology specimen demonstrated CC with clear margins. MRI and CT examinations done over the subsequent 17 months showed no evidence of recurrence. In conclusion ex vivo liver resection and Atx can be a viable option for cure among highly selected patients with CC.

Kupffer cells play an important role in controlling the growth and development of liver metastases. However, the pathway of Kupffer cells against tumor metastases is not clear. In the present study, we set up an experimental model to investigate the mechanisms on how Kupffer cells kill tumor cells which metastasize to the liver. Malignant glioma cells were cocultured with Kupffer cells or treated with culture medium collected from lipopolysaccharide (LPS)-activated Kupffer cells. The results showed that the interaction between Kupffer cells and malignant glioma cells significantly stimulated the generation of tumor necrosis factoralpha (TNFalpha). TNFalpha was mainly produced by Kupffer cells, as its level in culture medium obtained from LPS-treated Kupffer cells was not significantly different from that of malignant glioma cells treated with the same medium. Both Kupffer cells and LPS/Kupffer cell-conditioned supernatants induced expression of Fas and Fas ligand on malignant glioma cells. Subsequently a significant proportion of malignant glioma cells became apoptotic, as evidenced by positive staining of annexin V and propidium iodine and an increase in cellular DNA fragmentation. Therefore, this study supports a novel pathway of Kupffer cells against liver metastases, in which tumor cells were apoptotic via the Fas-Fas ligand system induced by TNFalpha released from Kupffer cells.

The possibility of using animal organs in transplantation has been attractive for a long time. Most experts believe that the pig will provide the most suitable solid organs and tissues for needy human recipients. Although porcine organs are known to be rapidly rejected by the process ‘hyperacute rejection’, there is now hope that several therapeutic strategies that are already available will overcome this problem. However, there are remaining hurdles to overcome. Delayed immune reaction, ethical concerns, physiological incompatibility and animal viruses will determine whether xenotransplantation will become a practical solution to the chronic shortage of allografts in clinical transplantation.

Hepatitis B is a major disease that causes serious public health problems worldwide. The loss of HBeAg expression due to point mutations or single nucleotide polymorphisms (SNPs) in the precore/basal core promoter region of the hepatitis B virus (HBV) is associated with hepatocellular cirrhosis and carcinoma. Simultaneous screening for these mutations is strongly advocated for monitoring disease development in HBV-infected patients. The aim of this study is to apply arrayed primer extension (APEX) for the detection of HBV SNPs at the precore/basal core promoter.We optimized APEX for simultaneous detection of eight potential sites of SNPs in the precore/basal core promoter region of HBV. The precore/basal core promoter regions of HBV from 36 HBV-infected patients were amplified by PCR. After purification and DNA fragmentation, the short, single-stranded HBV DNA fragments were allowed to hybridize with the oligonucleotides corresponding to the sites of SNPs immobilized on glass slides, followed by incorporation of different fluorescently labeled dideoxynucleotides. This allows fast and unequivocal discrimination between wild-type and mutant genotypes with high dideoxy-nucleotide incorporation efficiency, sensitivity, and specificity. The coexistence of both genotypes was also detected; this was undetected by DNA sequencing.The simultaneous detection of SNPs in HBV precore/basal core promoter by APEX enables large-scale diagnostic analysis, which can be extended to the whole HBV genome.

A patient with chronic hepatitis B underwent liver transplantation for end-stage cirrhosis. The donor liver graft had moderate steatosis and fibrosis. He was placed on lamivudine for hepatitis B prophylaxis but developed viral relapse due to emergence of a lamivudine-resistant mutant at week 72 posttransplantation. Results of liver biochemistry were normal liver histology revealed minimal steatosis and inflammation at weeks 151 and 128, respectively. This report illustrates that the use of a steatotic donor liver and the emergence of lamivudine resistance posttransplantation are not necessarily associated with significant graft damage. A marginal donor graft can be considered due to the donor shortage. Lamivudine monoprophylaxis for hepatitis B virus-related liver diseases post liver transplantation can be used in areas where hepatitis B immunoglobulin is not affordable.

Background: We aimed to investigate the clinical outcome of patients who develop lamivudine resistant hepatitis B virus mutants (YMDD mutants) after liver transplantation. Methods: Patients who received liver transplantation for hepatitis B-related liver diseases from 1999 to 2002 were studied. All patients received lamivudine monotherapy before and after liver transplantation. HBsAg and HBV DNA were regularly monitored, and YMDD mutation was detected by direct sequencing. Results: Twenty patients were followed up for median 94 wk (range: 15–177 wk) post-liver transplantation. Six patients developed YMDD mutants, and the cumulative probability of developing YMDD mutations post-liver transplantation was 21% in 1 yr and 34% in 2 yr. One patient developed YMDD mutants before liver transplantation and died of hepatitis reactivation and liver failure 15 wk post-transplantation. The other five patients developed YMDD mutants 32–72 wk after liver transplantation. Two of them developed severe hepatitis which responded promptly to adefovir dipivoxil. The remaining three patients with YMDD mutants had minimal to mild hepatitis. The cumulative survival for patients with YMDD mutants was 83% and 28% at 1 and 2 yr, respectively. Only one patient who did not develop YMDD mutants died at week 119 due to chronic rejection. The post-transplant survival for patients with YMDD mutants was significantly poorer than those without YMDD mutants (log rank test p = 0.083). Conclusions: The emergence of YMDD mutants after liver transplantation on lamivudine monoprophylaxis had wide range of clinical presentations and was associated with increased mortality.

This study aimed to investigate the factors associated with viral breakthrough among liver transplant recipients who receive lamivudine monoprophylaxis. Consecutive patients receiving liver transplantation for HBV-related liver disease from June 1999 to October 2000 were studied. All patients received lamivudine 100 mg daily pre- and post-transplant. Serum samples were collected before lamivudine treatment, before liver transplantation, and then every 3-6 months after liver transplantation. Lamivudine-resistant mutations at the YMDD motif of HBV P gene were detected by direct sequencing and HBV DNA was quantified by real-time polymerase chain reaction (PCR). Ten patients, 7 males and 3 females, aged 50.5 +/- 7.9 years, were studied. Three patients had fulminant hepatitis and 7 patients had end-stage cirrhosis before liver transplantation. Lamivudine was started at 4.5 (range 0-40) weeks before liver transplantation. The median post-transplant follow-up was 16 (range 12-23) months. Four patients developed YMDD mutations 10.5 (0-16) months after transplantation with relapse of viraemia (median 1,294, range 51-3,135 MEq/ml). All patients who developed YMDD mutants had end-stage liver cirrhosis, and HBV DNA were detectable on the day of liver transplantation (median 0.62, range 0.086-1.63 MEq/ml). On the contrary, all 3 patients transplanted for fulminant hepatitis did not have YMDD mutation. Among the 3 end-stage cirrhotic patients who had negative HBV DNA before liver transplantation, none developed YMDD mutation. In conclusion, patients transplanted for fulminant hepatitis B and cirrhotic patients in whom HBV DNA could be rendered PCR negative before liver transplantation are unlikely to develop YMDD mutation on lamivudine monoprophylaxis.

Kupffer cells, a liver organ-specific macrophage, play an important role in preventing the development of malignant tumors. The mechanism responsible for their tumoricidal activities is not completely known. In our study, we established in vivo models involving a rat malignant cell line, rat Kupffer cells and tumor implantation in nude mice. A series of relevant in vitro experiments were also carried out to determine possible pathways. LPS-activated Kupffer cells produced significant amounts of NO, TNFalpha and IFNgamma. Malignant cells treated with either Kupffer cells or culture supernatant of the activated Kupffer cells had an increase in caspase-8 activity. Implanted tumors originated from malignant cells treated with either Kupffer cells or culture supernatant of the activated Kupffer cells grew much smaller than those from malignant cells without treatment or treated with control supernatants. The alteration of anti-apoptotic Bcl-2 was inversely associated with the change of pro-apoptotic caspase-8 and their levels in the tumor tissues matched the size of the tumors and treatments they received. It appeared that the above changes resulted in an increase in cellular DNA damage and apoptosis seen in malignant cells. Therefore, Kupffer cells execute their anti-tumor effect via increasing the production of NO, TNFalpha and IFNgamma and these cytotoxic molecules inhibit the growth of tumor by damaging cellular DNA and inducing apoptosis that was featured by downregulation of Bcl-2 but upregulation of caspase-8.

Background: It is generally believed that positioning of the patient in a head-down tilt (Trendelenberg position) decreases the likelihood of a venous air embolism during liver resection. Methods: The physiological effect of variation in horizontal attitude on central and hepatic venous pressure was measured in 10 patients during liver surgery. Hemodynamic indices were recorded with the operating table in the horizontal, 20 degrees head-up and 20 degrees head-down positions. Results: There was no demonstrable pressure gradient between the hepatic and central venous levels in any of the positions. The absolute pressures did, however, vary in a predictable way, being highest in the head-down and lowest during head-up tilt. However, on no occasion was a negative intraluminal pressure recorded. Conclusion: The effect on venous pressures caused by the change in patient positioning alone during liver surgery does not affect the risk of venous air embolism.

Living related liver transplantation (LRLT) has gained popularity, especially in Asian countries as the primary mode of liver transplantation. LRLT, however, carries the inherent problem of potential donor harm. In view of reports of donor deaths and significant donor morbidity (as high as 67%), we examined donor complication rates in our LRLT program. All sixteen LRLT donors between February 2000 and January 2003 were retrospectively analyzed. The 16 donors (13 men, 3 women) of mean age 30 years (range, 18–49 years) included 5 donations from siblings, 2 from parents, and 9 from offsprings. The portion of liver donated was L hepatectomy (n = 4) R hepatectomy (n = 7), and Modified Extended R hepatectomy (n = 5) with the weight of resected liver being 618.9 g (range, 380–1000). The mean blood loss was 936 mL (range, 400–1900 mL), but only 2 donors required transfusion of banked blood. The mean intensive care unitstay was 1.06 days (range, 1–2 days) and the mean hospital stay was 9.12 days (range, 7–14 days). There was no case of reoperation and no mortality. There was no biliary or vascular complication. Four of 16 (25%) donors had a minor morbidity; 2 of 16 (12.5%) had a morbidity requiring intervention. In conclusion, with meticulous preoperative, intraoperative, and postoperative management, successful LRLT can be performed with minimal donor morbidities.

Severe acute respiratory syndrome (SARS) struck 1755 patients in Hong Kong and developed into a global health crisis. Although the World Health Organization and national health authorities are sparing no effort to contain the disease and to find a cure for the potentially deadly infection, SARS has an impact on our liver transplantation (LTx) program. Before the SARS outbreak, an average of 1 LTx was performed per month in our center. For 6 months since the outbreak, there had been no LTx performed. The intensive care unit had to be dedicated to patients with SARS. Two of the LTx team members were struck by SARS. A survey conducted among LTx recipients and their family members (n = 45) demonstrated symptoms of anxiety and stress in all. Some LTx recipients were treated at the Emergency Department for suspected SARS, which were later confirmed to be false alarms. Many LTx patients were too frightened to come back for follow-up. A new strain of coronavirus was identified as the causative agent. The origin of this virus is uncertain but the probability of zoonoses is being seriously discussed. Not only are immunosuppressed patients exposed to higher risk of infection, but also the waiting list mortality is also expected to increase. The SARS outbreak has demonstrated the vulnerability of an organ transplantation service and reminds us of the fearful possibility of zoonoses in future xeno-transplantation.

With a high prevalence of chronic hepatitis B and a low cadaveric organ donation rate, living donor liver transplantation (LDLT) remains the only option for many patients in Hong Kong. In such cases, the liver graft volume is smaller owing to a partial liver graft; therefore, a problem of small-for-size grafts often occurs. Between September 1999 and April 2003, 25 cadaveric, 16 living related, and 1 auto-LTs were performed at our center. The outcomes of LDLT were analyzed to assess the critical graft size and functional recovery. Among the 16 LDLT recipients (mean age, 44.4 +/- 14.4 years; mean weight, 61.9 +/- 11.4 kg), 1 patient received a graft from a donor left lobe (weight, 400 g) in an auxillary partial orthotopic LT (APOLT), 12 received right lobes, and 3 received left lobes. Besides the APOLT case, the overall graft/recipient weight ratio (GRWR) for the 15 LDLTs was 1.11 (0.76 to 1.75). The GRWR in the 25 cadaveric LTs was 1.92 (1.05 to 3.69) (P.001). Among the 12 successful LDLTs, there were 5 (41.7%) cases of small-for-size graft syndrome: 3 of 3 (100%) in GRWRor = 0.8%; 5 of 6 (83.3%) in GRWR1%; and 0 of 6 with GRWR1%. The initial post-LT graft function parameters were significantly higher among the LDLT group: International normalized ratio (INR), 1.42 vs 1.24, P = .03; alanine aminotransferase (ALT, 387 vs 201 IU/L, P = .005, and bilirubin, 170 vs 48 micromol/L, P.001 as compared to the cadaveric transplant group). Small-for-size graft syndrome can be avoided if GRWR1%, but often occurs when GRWR0.8%. Graft function in LDLT recovers more slowly than in cadaveric liver transplant.

Liver transplantation (LT) is an acceptable mode of treatment for selected patients with unresectable hepatocellular carcinoma (HCC). However, due to the scarcity of cadaveric donor organs, it is considered desirable for patients to opt for living donor liver transplantation (LDLT) or, for those not being transplanted soon, to have some form of tumor control therapy. Such an approach in our program is analyzed and reported. At our institution, 42 LTs were performed between October 1999 and April 2003. Of these, 18 recipients (15 men, 3 women) had 27 HCC. The average number and size of HCC was 1.59 (1 to 4) and 2.31 (0.2 to 6.5) cm, respectively. Thirteen (72%) patients were transplanted primarily for the HCC, whereas five (28%) others were incidental HCC cases. Seven patients (5 LRLT, 2 cadaveric LT) were transplanted soon after listing, and thus did not require tumor control therapy. Six patients waited for 11 (6 to 19) months before LT. Three patients underwent microwave coagulation therapy, and one had additional alcohol injections. One patient received the novel PIAF (cisplatin, interferon, adriamycin, and 5-FU) chemotherapy regimen followed by selective internal irradiation (SIR) treatment. One patient received conformal radiation therapy and another received SIR treatment before LT. Besides 2 postoperative deaths, the remaining 16 patients have been well, with a mean follow-up of 20.4 (3.6 to 41.2) months. In conclusion, for patients with unresectable HCC, in areas with poor cadaveric donor rate, living donation should be the first option. If a suitable live donor is not available, aggressive multimodality therapy is recommended while waiting for cadaveric LT.

THE HIGH prevalence of viral hepatitis B and its associated chronic complications in Hong Kong has produced many patients in need of liver transplantation. However, similar to other Asian countries, the persistent shortage of donor livers is a problem. Chinese people have the tradition of not parting with their organs after death. Consequently, requests for organ donation have only been successful in about 25% to 30% of cases during the past few years. Meanwhile, suboptimal management of potential donors has also resulted in graft losses. Potential organ donors are often not admitted to intensive care units, partly due to inadequate resources. Inadequate awareness of organ donation and transplantation within the medical profession has also been reported previously.