K. Höckerstedt

Human Herpesvirus-6 Infection After Liver Transplantation

A diagnosis of posttransplantation human herpesvirus-6 (HHV-6) infection was established for eight adult recipients among a liver transplantation patient population of 121. The diagnosis was based on serology and demonstration of HHV-6 specific antigens in liver biopsy specimens with use of monoclonal antibodies and immunoperoxidase staining. A significant graft dysfunction was recorded in association with serodiagnosis. HHV-6 early antigens, as well as HHV-6 variant B antigens, were detected retrospectively in all six available liver biopsy specimens. Histologic examination of biopsy specimens demonstrated acute rejection in 5 of the 8 patients, and 3 patients had portal lymphocyte infiltration. In five cases cytomegalovirus (CMV) infection was associated with HHV-6 infection; in four cases CMV antigens were also detected in the biopsy specimens. Two patients who had pure HHV-6 infection without CMV infection or rejection had significantly impaired graft function, with a positive antigen-detection test. Thus, HHV-6 may infect the liver allograft and cause graft dysfunction and may possibly be associated with rejection and/or CMV infection.

Colorectal Dysplasia and Carcinoma in Patients with Ulcerative Colitis and Primary Sclerosing Cholangitis

BACKGROUND The aim of this study was to evaluate the role of primary sclerosing cholangitis (PSC) as a cofactor in the dysplasia-carcinoma sequence in ulcerative colitis (UC). METHODS Forty-five patients with UC and concomitant PSC and 45 pair-matched control patients with UC only were examined for colorectal dysplasia and carcinoma. RESULTS The median duration of UC was 11 years in the group with UC and PSC and 15 years in the control group. Thirteen of the 45 patients (29%) with UC and PSC had colorectal neoplasia: 4, carcinoma; 2, high-grade dysplasia; and 7, low-grade dysplasia. Four of the 45 control patients (9%) had neoplastic findings: 1, carcinoma; 1, high-grade dysplasia, and 2, low-grade dysplasia (P < 0.05). CONCLUSION The results suggest that the risk of colorectal dysplasia and carcinoma in patients with UC is increased by concomitant PSC.

Gastric blood flow, tissue gas tension and microvascular changes during hemorrhage-induced stress ulceration in the pig

Various features of blood supply to the gastric mucosa were studied in the piglet stomach during stress ulceration induced by hemorrhagic shock. Gastric blood flow, as measured by the radioactive microsphere technique, significantly decreased during shock, but no major change occurred in the gastric function of total cardiac output. There was no difference in the magnitude of the decrease of mucosal blood flow between the nonulcerating antral mucosa and the more readily ulcerating corpus or fundic mucosa. At the same time, a significant decrease in tissue partial pressure of oxygen and increase in tissue partial pressure of carbon dioxide occurred, but again no difference was observed between the antrum and the corpus. Microangiographic studies demonstrated a clearly diminished filling of the arterial and capillary bed of the gastric mucosa during shock, suggesting intense vasoconstriction, thrombosis of the mucosal blood vessels, or both. These changes were more prominent in the corpus portion of the stomach than in the antrum. At the site of mucosal lesions, the filling defects persisted even after the shock, suggesting permanent thrombosis of the blood vessels.

Human herpesvirus-6 infection is associated with adhesion molecule induction and lymphocyte infiltration in liver allografts

BACKGROUND/AIMS Human herpesvirus-6 (HHV-6) infection has been recently described in liver transplants. HHV-6 may infect the transplant and cause graft dysfunction. Some association between HHV-6 and rejection has also been recorded. We have now investigated the possible involvement of HHV-6 in the intragraft immunological processes, adhesion molecules induction and lymphocyte activation. METHODS HHV-6 was detected in liver biopsies of 19 patients transplanted in the period from 1996 to 2000. Patients with other infections or rejection were excluded from the study. Finally, 19 biopsies of eight allografts with pure HHV-6 infection were available. Adhesion molecules (ICAM-1, VCAM-1, ELAM-1) and their ligands (LFA-1, VLA-4, sLeX) and lymphoid activation markers (MHC class II, IL-2R) were demonstrated in liver biopsies by immunohistochemistry. Five biopsies from patients with normal graft function and without rejection or infection were used as controls for immune staining, and ten biopsies with acute rejection but without infection were used as positive controls. RESULTS Biopsy histology demonstrated mild to moderate lymphocyte infiltration associated with HHV-6 infection. HHV-6 significantly (P < or = 0.05) increased the vascular expression of ICAM-1 and VCAM-1, and the number of graft infiltrating lymphocytes positive for LFA-1, VLA-4 and class II antigens. A total of 3/8 grafts developed chronic rejection. CONCLUSIONS HHV-6 infection increased adhesion molecule expression and lymphocyte infiltration in liver allografts.

HLA antigens in ulcerative colitis and primary sclerosing cholangitis

The aims of this study were to find out whether the alleles of the HLA class I or II region are associated with susceptibility to ulcerative colitis, and to show whether there is a difference or similarity in HLA associations between primary sclerosing cholangitis and ulcerative colitis. HLA‐A, B, C and DR antigens were studied using the standard lymphocyte microcytotoxicity test in 24 Finnish patients with primary sclerosing cholangitis, 77 patients with ulcerative colitis, and 106 controls. HLA‐B8 (54%) and DR3 (60%) were associated with primary sclerosing cholangitis. HLA‐DR1 (46%) and DR6 (20%) seemed more common in ulcerative colitis than in controls. A positive association with Cw7 was common to both ulcerative colitis (25%) and primary sclerosing cholangitis (33%). Our results indicate that ulcerative colitis is more heterogeneous than primary sclerosing cholangitis in its HLA‐DR associations.

Comparison of plasma polymerase chain reaction and pp65-antigenemia assay in the quantification of cytomegalovirus in liver and kidney transplant patients

BACKGROUND Cytomegalovirus (CMV) is a significant problem in transplantation. The antiviral treatment is based on the clinical symptoms and the rapid laboratory diagnosis. Although polymerase chain reaction (PCR) methods have already been widely used, the clinical correlation of the findings is not clear. OBJECTIVE The objective of this study was to investigate the usefulness of a quantitative plasma PCR test and compare it with the pp65-antigenemia test in the detection of clinically significant CMV infections in liver and kidney transplant patients. STUDY DESIGN The clinical material consisted of 253 consecutive blood samples was tested using a quantitative polymerase chain reaction test, Cobas Amplicor CMV Monitor (Roche) and pp65 antigenemia assay. Plasma was used for PCR and leucocytes were used for the antigenemia test. RESULTS CMV was detected in 89 out of 253 blood samples by one or both methods. PCR detected 78 (range 274-165000 copies/ml) and pp65 antigenemia test 79 (range 1-1500 positive cells/50000) of the positive findings. The sensitivity and specificity of PCR test was 86 and 94%, respectively. The PCR detected all clinically significant CMV infections (>10 positive cells in pp65 test) and infections which required antiviral treatment. In addition, the correlation between the two tests was almost linear. CONCLUSIONS The quantitative PCR appears to be a suitable alternative to diagnose and monitor CMV infections in transplant patients.

Expression of adhesion molecules and their ligands in liver allografts during cytomegalovirus (CMV) infection and acute rejection

Abstract  Vascular adhesion molecules and their ligands are important in leukocyte‐endothelial cell interactions and in T‐cell activation of rejection cascade. Also, cytomegalovirus (CMV) infection is suggested to be involved in the mechanisms of rejection. In this study, the expression of vascular adhesion molecules ICAM‐1, VCAM‐1 and ELAM‐1 in the liver allografts, the number of leukocytes positive for their ligands LFA‐1, VLA‐4 and SLex, and activation markers (class II, IL2‐receptor) were investigated in liver allografts during CMV infection and acute rejection and compared to grafts with normal function and histology. The adhesion molecules, their ligands and activation markers were demonstrated from liver biopsy frozen sections by the immunoperoxidase technique and monoclonal antibodies. A significant induction of ICAM‐1 and VCAM‐1 was seen in vascular and sinusoidal endothelium associated with both CMV and rejection, and induction of ELAM‐1 in vascular endothelium in rejection only. In both cases, the number of leukocytes expressing LFA‐1 was significantly increased, but VLA‐4‐positive cells were more characteristic for CMV and SLex‐positive cells more for rejection. IL2‐receptor positivity was practically seen in rejection only, but class II‐expressing cells were increased during both CMV infection and rejection. In conclusion, adhesion molecules were induced and the infiltrating cells expressed their ligands both in liver rejection and during CMV infection, although the expression pattern was slightly different.

Liver transplantation for unresectable hepatocellular carcinoma in normal livers

BACKGROUND & AIMS The role of liver transplantation in the treatment of hepatocellular carcinoma in livers without fibrosis/cirrhosis (NC-HCC) is unclear. We aimed to determine selection criteria for liver transplantation in patients with NC-HCC. METHODS Using the European Liver Transplant Registry, we identified 105 patients who underwent liver transplantation for unresectable NC-HCC. Detailed information about patient, tumor characteristics, and survival was obtained from the transplant centers. Variables associated with survival were identified using univariate and multivariate statistical analyses. RESULTS Liver transplantation was primary treatment in 62 patients and rescue therapy for intrahepatic recurrences after liver resection in 43. Median number of tumors was 3 (range 1-7) and median tumor size 8 cm (range 0.5-30). One- and 5-year overall and tumor-free survival rates were 84% and 49% and 76% and 43%, respectively. Macrovascular invasion (HR 2.55, 95% CI 1.34 to 4.86), lymph node involvement (HR 2.60, 95% CI 1.28 to 5.28), and time interval between liver resection and transplantation < 12 months (HR 2.12, 95% CI 0.96 to 4.67) were independently associated with survival. Five-year survival in patients without macrovascular invasion or lymph node involvement was 59% (95% CI 47-70%). Tumor size was not associated with survival. CONCLUSIONS This is the largest reported series of patients transplanted for NC-HCC. Selection of patients without macrovascular invasion or lymph node involvement, or patients ≥ 12months after previous liver resection, can result in 5-year survival rates of 59%. In contrast to HCC in cirrhosis, tumor size is not a predictor of post-transplant survival in NC-HCC.

Early molecular adsorbents recirculating system treatment of Amanita mushroom poisoning.

Acute poisoning due to ingestion of hepatotoxic Amanita sp. mushrooms can result in a spectrum of symptoms, from mild gastrointestinal discomfort to life‐threatening acute liver failure. With conventional treatment, Amanita phalloides mushroom poisoning carries a substantial risk of mortality and many patients require liver transplantation. The molecular adsorbent recirculating system (MARS) is an artificial liver support system that can partly compensate for the detoxifying function of the liver by removing albumin‐bound and water‐soluble toxins from blood. This treatment has been used in acute liver failure to enable native liver recovery and as a bridging treatment to liver transplantation. The aim of the study is to evaluate the outcome of 10 patients with Amanita mushroom poisoning who were treated with MARS. The study was a retrospectively analyzed case series. Ten adult patients with accidental Amanita poisoning of varying severity were treated in a liver disease specialized intensive care unit from 2001 to 2007. All patients received MARS treatment and standard medical therapy for mushroom poisoning. The demographic, laboratory, and clinical data from each patient were recorded upon admission. The one‐year survival and need for liver transplantation were documented. The median times from mushroom ingestion to first‐aid at a local hospital and to MARS treatment were 18 h (range 14–36 h) and 48 h (range 26–78 h), respectively. All 10 patients survived longer than one year. One patient underwent a successful liver transplantation. No serious adverse side‐effects were observed with the MARS treatment. In conclusion, MARS treatment seems to offer a safe and effective treatment option in Amanita mushroom poisoning.

Effect of the aetiology and severity of liver disease on oral health and dental treatment prior to transplantation.

Elimination of dental infection foci has been recommended before liver transplantation (LT) because lifelong immunosuppression may predispose to infection spread. Association between pre‐LT oral health and the aetiology and severity of chronic liver disease (CLD) was investigated retrospectively. A total of 212 adult patients (median age 51.1) who had received LT during 2000–2006 in Finland were included. Their oral health had been pre‐operatively examined. Patients were divided into seven different CLD groups. Common indications for LT were primary sclerosing cholangitis (PSC 25.5%), alcohol cirrhosis (ALCI 17.5%) and primary biliary cirrhosis (PBC 14.6%). Patients were also categorized by the Model for End stage Liver Disease (MELD) scoring system. Medical, dental and panoramic jaw x‐ray data were analysed between groups. PBC patients had the lowest number of teeth with significant difference to PSC patients (19.7 vs. 25.6, P < 0.005, anova, t‐test). ALCI patients had the highest number of tooth extractions with significant difference in comparison to PSC patients (5.6 vs. 2.5, P < 0.005). Lower MELD score resulted in fewer tooth extractions but after adjusting for several confounding factors, age was the most important factor associated with extractions (P < 0.005). The aetiology of CLD associated with the oral health status and there was a tendency towards worse dental health with higher MELD scores.