Analysis of human liver disease using a cluster of differentiation (CD) antibody microarray.

BACKGROUND: A CD antibody microarray has been previously developed allowing semi-quantitative identification of greater than 80 CD antigens on circulating leucocytes from peripheral blood samples. This assay, which uses a live cell-capture technique, enables an extensive leucocyte immunophenotype determination in a single analysis and to date this has been used successfully to characterise diseases including human leukaemias and HIV infection. AIMS: To determine CD antigen expression profiles for patients with various liver diseases and to look for preserved disease-specific signatures. METHODS: Three liver disease groups including hepatitis C (HCV) (n = 35), non-alcoholic steatohepatitis (NASH) (n = 21) and alcohol-related liver disease (n = 14) were compared with a normal group (n = 23). Hierarchal Clustering (HCL) and Principal Component Analysis (PCA) of the data revealed distinct binding patterns for patients with and without cirrhosis. RESULTS: Patients with cirrhosis and portal hypertension compared with those without cirrhosis had significantly reduced expression of several markers of T-cell function including CD45, CD8, CD28 and TCR α/ß. Disease prediction algorithms based on the expression data were able to discriminate cirrhotics from non-cirrhotics with 71% overall success, which improved to 77% when only patients with HCV were considered. CONCLUSIONS: These results demonstrate disease-specific consensus patterns of expression of CD antigens for patients with chronic liver disease, suggesting that the CD antibody array is a promising tool in the analysis of human liver disease, and with further refinement may have future research and clinical utility.

Locoregional therapies for hepatocellular carcinoma: which patients are most likely to gain a survival advantage?

BACKGROUND AND AIM: Locoregional therapies for hepatocellular carcinoma (HCC) are considered to confer a survival advantage, however, the patient group that should be targeted is not clearly defined. This study aimed to determine the impact on survival of locoregional therapies compared with supportive care, within prognostic categories as stratified by the Cancer of the Liver Italian Program (CLIP) scoring system. METHODS: A prospective database was used to identify those patients who were treated with either locoregional therapy (n = 128) or supportive care (n = 92). Survival analysis was performed for groups matched by CLIP score at presentation. Comparison of important prognostic factors was undertaken and univariate and multivariate analysis was performed to assess determinants of survival. RESULTS: Use of locoregional therapies was only associated with a survival benefit in patients with a CLIP score of 1 or 2. In this group, the median survival in patients who received locoregional therapies was 25.0 months (95% confidence interval 22.7-27.4) compared with 8.9 months (95% confidence interval 7.3-10.5) for supportive care (P = 0.001). For patients with CLIP scores of 3 or greater, no survival benefit of locoregional therapies was observed. Multivariate analysis revealed locoregional intervention, CLIP score, tumor symptoms, alpha-fetoprotein level, bilirubin and alkaline phosphatase level as independent prognostic indicators. CONCLUSION: Locoregional therapies should be targeted specifically to patients with non-advanced hepatocellular carcinoma as assessed by validated scoring systems. Use of these therapies in patients with advanced disease does not appear to be associated with a survival benefit and may expose patients to unnecessary harm.

Early high peak hepatitis C viral load levels independently predict hepatitis C-related liver failure post-liver transplantation.

The aim of this study was to examine the importance of the serum hepatitis C viral load within the first year post-liver transplant in determining posttransplant survival. A retrospective analysis of 118 consecutive hepatitis C virus-positive liver transplant recipients who received an allograft from January 1997 to September 2005 was undertaken with a median duration of follow-up of 32.4 months. Univariate and multivariate analyses were used to examine the effects of recipient, donor, surgical, and viral factors on posttransplant outcomes. A total of 620 viral load estimations were undertaken in the first 12 months following transplantation. Patient and graft survival rates at 1, 3, and 5 years were 87.8%, 79.9%, and 70.1% and 87.0%, 79.2%, and 68.2%, respectively. According to multivariate analysis, a peak viral load > or = 10(7) IU/mL (P = 0.004; hazard ratio, 8.68; 95% confidence interval, 2.04-37.02) and exposure to antirejection therapy (P = 0.05; hazard ratio, 2.26; 95% confidence interval, 1.01-5.38) were both independent predictors of diminished patient and graft survival and hepatitis C-related allograft failure. The only other independent predictor of hepatitis C virus-related outcome after transplant was azathioprine use, which was associated with improved outcomes (P = 0.04; hazard ratio, 0.25; 95% confidence interval, 0.07-0.91). A peak viral load in the first year after transplant of >10(8), 10(7) to 10(8), and <10(7) IU/mL was associated with a mean survival of 11.8, 70.6, and 89.1 months respectively (P < or = 0.03). The results emphasize the importance of high viral loads in the early posttransplant period as an independent predictor of recipient outcomes.

Interactions between primary sclerosing cholangitis and inflammatory bowel disease: implications in the adult liver transplant setting.

INTRODUCTION: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease which is associated with inflammatory bowel disease (IBD) in most cases. As there is currently no medical therapy which alters the natural history of PSC, liver transplantation may be required. Areas covered: We searched for articles in PubMed and critically reviewed current literature on the interrelationship between PSC and IBD with a specific focus on considerations for patients in the liver transplant setting. Expert commentary: PSC is an uncommon disease which limits available studies to be either retrospective or contain relatively small numbers of patients. Based on observations from these studies, the behavior and complications of PSC and IBD impact on each other both before and after a liver transplant. Both these autoimmune conditions and their associated cancer risk also influence patient selection for transplantation and may be impacted by immunosuppression use post-transplant. Hence, a complex interplay exists between PSC, IBD and liver transplantation which requires clarification with ongoing research.

Patients with non-viral liver disease have a greater tumor burden and less curative treatment options when diagnosed with hepatocellular carcinoma.

AIM: To assess the impact of underlying liver disease etiology on the presenting features and outcomes in a large cohort of patients with hepatocellular carcinoma (HCC). METHODS: A prospective database of all patients with HCC was established from 1998 to March 2012. One thousand and seventy-eight patients were categorized into three groups, based on the etiology of their liver disease: hepatitis B virus (HBV), hepatitis C virus (HCV) and non-viral liver disease (NVLD). Overall survival was determined by Kaplan Meier analysis to time of death or last follow-up. RESULTS: HCC patients with HCV (85%) were more likely to be diagnosed as part of a surveillance program, compared to HBV or NVLD (both 71%) (P < 0.001). Patients with NVLD were more likely to receive best supportive care (29%) compared to those with HBV (21%) or HCV (20%) (P < 0.02). Twelve percent of NVLD and 13% of HBV patients underwent liver transplantation compared to 21% of HCV patients (P = 0.001). Median survival from presentation was lowest in NVLD (1.7 years) when compared to HBV (2.8 years) and HCV (2.6 years) (P < 0.05). In multivariate analysis, independent predictors of survival included Child Turcotte Pugh score, size of dominant lesion, absence of vascular invasion, and management with surgical resection or liver transplantation. Patient age and the etiology of the underlying liver disease were not independent predictors of survival. CONCLUSION: Patients with NVLD and HCC were less likely to be enrolled in a HCC surveillance program and are less likely to have curative therapies such as liver resection and transplantation after diagnosis with HCC, when compared to patients with Hepatitis B and Hepatitis C.

Passive transfer of nut allergy after liver transplantation.

An anaphylactic reaction to cashew nut developed in a nonatopic 60-year-old man 25 days after receiving a liver allograft from a 15-year-old atopic boy who died of anaphylaxis after peanut ingestion. The liver recipient had no history of nut allergy. Posttransplantation skin prick test results were positive for peanut, cashew nut, and sesame seed, and the donor had allergen-specific IgE antibodies to the same 3 allergens. Contact tracing of the recipients of other solid organs from the same donor disclosed no other development of allergic symptoms after ingestion of peanut or cashew nut. Results of molecular HLA typing did not detect any donor-origin leukocytes in the recipient after transplantation, which excluded peripheral microchimerism. The patient inadvertently ingested peanut-contaminated food and suffered a second anaphylactic reaction 32 weeks after the transplantation. This case illustrates that transfer of IgE-mediated hypersensitivity can occur after liver transplantation and have potentially serious consequences. We therefore recommend that organ donors undergo screening for allergies, and that recipients be advised regarding allergen avoidance.

Liver transplantation for viral hepatitis.

Viral hepatitis is associated with two forms of liver failure that may require liver transplantation: fulminant hepatic failure associated with all forms of acute viral hepatitis and chronic liver failure as a result of chronic hepatitis B and C infection (or both). This review briefly discusses liver transplantation for fulminant hepatitis but focuses on transplantation for hepatitis B- and hepatitis C-associated cirrhosis.

Analysis of Post-Liver Transplant Hepatitis C Virus Recurrence Using Serial Cluster of Differentiation Antibody Microarrays.

BACKGROUND: Hepatitis C virus (HCV) reinfection of the liver allograft after transplantation is universal, with some individuals suffering severe disease recurrence. Predictive markers of recurrent disease severity are urgently needed. In this study, we used a cluster of differentiation (CD) microarray to predict the severity of HCV recurrence after transplantation. METHODS: The CD antibody microarray assays of live leukocytes were performed on peripheral blood taken in the first year after transplantation. The results were grouped into phases defined as; Pre-transplant (day 0), Early (day 3 to week 2), Mid (week 4 to week 10), and Late (week 12 to week 26). Hepatitis C virus severity was based on fibrosis stages in the first 2 years (F0-1 mild and F2-4 severe). RESULTS: Serial blood samples from 16 patients were taken before and after liver transplantation. A total of 98 assays were performed. Follow-up was 3 years or longer. Comparing recurrence severity, significantly greater numbers of CD antigens were differentially expressed on the pretransplant samples compared to any posttransplant timepoints. Five differentially expressed CD antigens before transplantation (CD27 PH, CD182, CD260, CD41, and CD34) were significantly expressed comparing severe to mild recurrence, whereas expression of only CD152 was significant in the late phase after transplantation. No relationship was observed between the donor or recipient interleukin-28B genotypes and HCV recurrence severity. CONCLUSIONS: This study shows that circulating leukocyte CD antigen expression has utility in assessing recurrent HCV disease severity after liver transplantation and serves as a proof of principle. Importantly, pretransplant CD antigen expression is most predictive of disease outcome.

Improving access to HCV treatment: external jugular venepuncture can overcome problems with difficult venous access.

Many patients requiring antiviral treatment of chronic hepatitis C (HCV) have a background of significant injection drug use (IDU). In a proportion of patients, IDU results in difficulty with blood collection from conventional sites. We audited patients from the Liver Clinics and Drug Health Pharmacotherapy Service of The Royal Prince Alfred Hospital (RPAH) to determine the incidence of difficulty with blood collection. This survey identified the need for an innovative venous access strategy to better manage this group of patients. An external jugular venepuncture (EJV) protocol and education package was developed in collaboration with the Department of Anaesthetics, Gastroenterology and Liver Centre and HCV clinical nurse consultants (CNC). RPAH policy and procedure committee approved the protocol and patient information sheet. Patients with a history of difficulty with blood collection were eligible for the protocol. Patient satisfaction surveys were conducted. The initial survey of patients from the liver clinics and pharmacotherapy service identified that 48 percent had difficulty with blood collection from conventional sites. In the period October 2002 to July 2006, 29 patients (89 percent with history of IDU) were referred for EJV assessment. Major indications for EJV were for blood testing for initiation and monitoring of antiviral therapy and ongoing assessment of HCV infected patients. No adverse events resulted from the procedure. All patients surveyed report high levels of satisfaction with the technique compared to previous venous access attempts. EJV improves access to antiviral therapy and is a safe and effective technique for patients with difficult venous access (DVA). In addition, we have utilised EJV for post-transplant care of patients and used external jugular vein cannulation as vascular access for contrast imaging in hepatocellular carcinoma (HCC) assessment.

Outcome of patients with hepatocellular carcinoma referred to a tertiary centre with availability of multiple treatment options including cadaveric liver transplantation.

UNLABELLED: Hepatocellular carcinoma (HCC) is a primary cancer of the liver with an established causal link to viral hepatitis and other forms of chronic liver disease. AIMS: The aim of this study was to analyse the determinants of outcome in patients with HCC referred to a tertiary centre for management. METHOD: Two hundred and thirty-five prospective patients with HCC and minimum 12-month follow-up were studied. RESULTS: The cohort was heterogeneous, with 52% Caucasian, 40% Asian and 5% of Middle-Eastern origin. Independent predictors of outcome included tumour size and number, the presence of ascites or portal vein thrombosis, alpha-foetoprotein >50 U/L and an impaired performance status. Treatment was determined on an individual case basis by a multidisciplinary tumour team. Surgical resection was primary treatment in 43 patients, liver transplantation in 40 patients, local ablation (percutaneous radiofrequency ablation or alcohol injection) in 33 patients, transarterial chemoembolisation in 33 patients, chemotherapy or other systemic therapy in 30 patients and no treatment in 56 patients. After adjustment for significant covariates, both liver transplantation (P<0.001) and surgical resection (P=0.029) had a significant effect on patient survival compared with no treatment, but local ablation (P=0.410) and chemoembolisation (P=0.831) did not. Liver transplantation resulted in superior overall and, in particular, disease-free survival compared with surgical resection (disease-free survival 84 vs 15% at 5 years). CONCLUSION: In conclusion, both surgical resection and liver transplantation significantly improve the survival of patients with HCC, but improvements need to be made to the delivery of loco-regional therapy to enhance its effectiveness.

Long-term lamivudine monotherapy prevents development of hepatitis B virus infection in hepatitis B surface-antigen negative liver transplant recipients from hepatitis B core-antibody-positive donors.

BACKGROUND: Liver transplantation from hepatitis B core-antibody (HBcAb)-positive donors to hepatitis B surface-antigen (HBsAg)-negative recipients has been associated with a risk of hepatitis B virus (HBV) infection in the absence of antiviral prophylaxis. The aim of this study is to assess the efficacy of long-term lamivudine monotherapy to prevent development of HBV infection in HBsAg-negative recipients of liver allografts from HBcAb-positive donors. METHODS: From 315 cadaveric adult liver transplantations performed at our unit between July 1999 and March 2005, 18 recipients (5.7%) received liver allografts from HBcAb-positive donors, 13 of whom were HBsAg-negative pre-transplantation. The recipients consisted of four females and 14 males, age range 28-65 yr (median 49.5 yr). Post-transplantation, HBsAg-negative recipients were administered lamivudine 100 mg daily long term. HBsAg-positive recipients were administered low-dose hepatitis B immunoglobulin (HBIg) and lamivudine according to our usual protocol. Standard post-transplantation immunosuppression was given. Recipients were followed up regularly (range 2-69 months, median 21 months) for development of de novo HBV infection. RESULTS: Ten HBsAg-negative recipients received long-term lamivudine. One patient (HBcAb and HBsAb positive pre-transplant) did not receive lamivudine and, in two patients, lamivudine was discontinued following urgent re-transplantation for primary graft non-function. All 13 of the HBsAg-negative recipients were still alive, with no evidence of HBV infection at the end of follow-up. CONCLUSION: Long-term lamivudine monotherapy was effective in preventing development of HBV infection in HBsAg-negative liver transplant recipients from HBcAb-positive donors.

Hereditary lysozyme amyloidosis: spontaneous hepatic rupture (15 years apart) in mother and daughter. role of emergency liver transplantation.

Hepatic rupture is a rare condition, and treatment options are very limited. We report a case of hepatic rupture secondary to hereditary lysozyme amyloidosis that was successfully treated by liver transplantation. The mother of this patient had presented in an identical fashion 15 years earlier in the pretransplant era and died very rapidly.

Severe autoimmune hepatitis first presenting in the early post partum period.

BACKGROUND & AIMS: Autoimmune hepatitis (AIH) may run an aggressive clinical course if untreated. The influence of pregnancy on AIH is variable. Both flares in disease activity and remissions, often followed by a post partum flare, are well recognized. In contrast, definite AIH first presenting in the early post partum period has not been reported. METHODS: We discuss a case series of 5 patients who developed severe AIH within 4 months post partum. RESULTS: The diagnosis of AIH was definite based on internationally accepted criteria. Liver injury responded to conventional immunosuppressive therapy in all patients. Immune reactivation in the early post partum period may contribute to this entity. CONCLUSIONS: AIH should be considered in the differential diagnosis of liver dysfunction first presenting in the early post partum period.

Clinical experience gained from the use of 120 steatotic donor livers for orthotopic liver transplantation.

Steatosis of the donor liver is known to impact on patient and allograft outcome after orthotopic liver transplantation (OLT). The aim of this study is to evaluate the effect of increasing grades of cadaveric donor liver steatosis on recipient outcome. Between January, 1986 and December, 2000, 120 OLTs were performed with 72 mild, 25 moderate, and 23 severe steatotic donor livers. Donors of steatotic livers were more likely to be older (P =.001) and have died of intracerebral haemorrhage than donors of nonsteatotic livers. Initial poor graft function (IPF) was more common in donor livers with either moderate or severe steatosis than in donor livers with mild steatosis (P =.03). Primary graft nonfunction (PNF) occurred in only 1 donor liver with severe steatosis. PGE1 (PGE1) usage was higher in recipients of donor livers with moderate or severe steatosis versus donor livers with mild steatosis (P =.001). Allograft loss was greater at 1 year both in the moderate and severe (P =.03) steatotic liver groups. Patient survival at 3 months and overall allograft survival both were impacted negatively by increasing grades of donor liver steatosis (P =.02, P =.03). Three-month allograft survival was reduced in the steatotic donor livers if the donor was 50+ years old (P =.033). Recipient status at OLT (P =.001) and donor steatosis (P =.046) impacted on 30 day allograft survival (multivariate analysis). In conclusion, increasing grades of donor liver steatosis were associated with worse IPF and increased PGE1 usage. There was a negative impact of steatosis on both recipient and early allograft survival.

p53, deleted in colorectal cancer gene, and thymidylate synthase as predictors of histopathologic response and survival in low, locally advanced rectal cancer treated with preoperative adjuvant therapy.

PURPOSE: Adjuvant therapy, either preoperatively or postoperatively, and modifications of surgery have been used to try to improve outcome of surgery for rectal cancer in regard to both local recurrence and survival. Assessment of prognosis in patients after resection is currently primarily based on clinicopathologic factors. These predict the subsequent behavior of the tumor only imperfectly. The aim of this study was to evaluate three potential molecular genetic markers of prognosis (p53, deleted in colorectal cancer gene, and thymidylate synthase) in Dukes Stage B and C low rectal tumors treated with adjuvant therapy and to determine whether they correlate with survival, local recurrence, or the pathologic response to adjuvant therapy (assessed by extent of tumor regression and tumor down-staging). METHODS: Sixty locally advanced low rectal tumors resected after preoperative chemoradiotherapy or radiotherapy alone were studied by immunohistochemical staining for p53, deleted in colorectal cancer gene, and thymidylate synthase. In addition, p53 gene mutations were sought by polymerase chain reaction-single-strand conformation polymorphism analysis. These results were correlated with survival, local recurrence, and pathologic response to adjuvant therapy. RESULTS: Lack of thymidylate synthase staining by immunohistochemistry was associated with tumor down-staging after preoperative chemoradiotherapy but not after radiotherapy or for these two combined groups. There was no correlation between p53, deleted in colorectal cancer gene, or thymidylate synthase immunohistochemical staining or between p53 polymerase chain reaction-single-strand conformation polymorphism and local recurrence or survival in locally advanced low rectal cancers treated with preoperative adjuvant therapies. CONCLUSION: Prediction of prognosis in patients with locally advanced low rectal cancers treated with preoperative adjuvant therapies continues to be problematic. Thymidylate synthase immunohistochemistry appears to be the most promising factor of those assessed in predicting tumor down-staging after preoperative chemoradiotherapy for locally advanced low rectal cancers.