Persistent T-cell activation and clinical correlations in patients with ANCA-associated systemic vasculitis.

BACKGROUND: Although in antineutrophil cytoplasmic autoantibodies (ANCA)-associated systemic vasculitis (AASV) patients, activation of T-cells has been described, persistence of these alterations has not been well characterized. This study was conducted to define persistent T-cell activation (PTA) in AASV patients and to assess whether this correlates with disease activity, disease severity, age or therapy. METHODS: The expression of CD4, CD45RO, CD25, CD26, CD28, CCR7 and HLA-DR was examined longitudinally in 38 consecutive AASV patients. Clinical parameters were compared by univariate and multiple analysis and Kaplan-Meier curves for relapse-free survival were calculated. RESULTS: PTA could be defined as either of two activation phenotypes, i.e. a low percentage of CD4+ CD45RO- T-cells or a high percentage of CD25 in the na?ve CD4+ population (n = 26), since only these phenotypes were stable over time and were not associated with active disease. In patients with PTA, major organ involvement was significantly more often found than in patients without PTA. Moreover, the cumulative cyclophosphamide dose (26.86 vs 8.53 P < 0.01) was significantly increased in these patients, suggesting that PTA was associated with disease severity. In general, patients with PTA were older than those without (62.92 +/- 9.4 years vs 48.42 +/- 16.9 years respectively, P < 0.01). PTA was independent of disease duration. Interestingly, patients with a low percentage of CD4+CD45RO- T-cells were significantly more often diagnosed as microscopic polyangiitis (P < 0.01). CONCLUSION: We identified two independent phenotypes of T-cell activation in AASV patients. These phenotypes are persistent and do not reflect disease activity. PTA predominantly occurs in patients with severe disease. This might explain the higher cumulative cyclophosphamide dose found in these patients.     

Elevated soluble CD30 characterizes patients with hepatitis C virus-induced liver allograft cirrhosis

Hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (OLT) significantly accelerates progression to allograft cirrhosis. Current biochemical parameters to monitor progression of chronic HCV after OLT have yielded low specificity and sensitivity. Here we investigated the HCV-specific immunity and serum levels of soluble CD30 (sCD30), a novel marker of Th2 immunity, in patients with and without allograft cirrhosis. Patients with hepatic inflammation but no cirrhosis (HIN, n=20) revealed elevated serum interferon (IFN)-gamma and high frequency of IFN-gamma producing CD4 T(h1) cells compared to those with hepatic cirrhosis (HFC, n=20) that had high interleukin (IL)-5 and IL-5 producing CD4 T(h2) cells. Patients with HFC, but not HIN, were found to have significantly higher levels of sCD30. Therefore, we conclude that lack of optimal Th1-type CD4 T cells is associated with HCV-induced allograft cirrhosis. Further, sCD30 may represent a novel marker for surveillance of hepatic cirrhosis in transplant recipients with chronic HCV infection.     

Lack of effect of chronic hepatitis C virus infection on T-cell cytokine production in chronic hemodialysis patients.

It has been shown that chronic hemodialysis modifies, to some extent, the normal immune response by both T and B lymphocytes elicited by antigenic stimulation, e.g. by impairing the T-cell-dependent response after vaccination. A new technique, i.e. flow cytometry, enables to assess intracytoplasmically, at the single cell level, the production of a given cytokine. By using it, we studied in healthy volunteers (HV) and in chronic hemodialysis (CHD) patients, with respect to their hepatitis C virus (HCV) status, the production by the T lymphocytes of type 1, and type 2 cytokines. We studied the following cytokines (CK): IL-2, IL-4, IL-5, IL-6, IL-10, IFN-gamma and TNF-alpha in the T-cell lymphocytes (whole, CD4+ and CD8+). There were 13 HV and 59 CHD patients (36 HCV(-) and 23 HCV(+)). Amongst the latter, there were 32 men and 27 women, aged 59.5 +/- 2 years, undergoing CHD since 70 +/- 9.4 months. We found that: (1) the total number of lymphocytes as well as those expressing CD3, CD4, or CD19 were significantly decreased in CHD patients as compared to those from HV; (2) the total number of lymphocytes as well as their different subsets were similar in HCV(+) and in HCV(-) CHD patients; (3) the frequency of T-cell-expressing IL-5 or IL-10 was always low (<1%) in both HV and CHD groups; (4) overall in CHD patients, the mean percentages of T lymphocytes expressing IL-2, IL-4, IFN-gamma or TNF-alpha were respectively 31 +/- 13, 2.5 +/- 1.3, 28 +/- 12 and 34 +/- 11% and were not statistically different between HCV(+) and HCV(-) patients; (5) IL-2 was mainly produced by CD4+ T cells, whereas IFN-gamma was produced by CD8+ T cells, in both HV and CHD groups, and (6) the lymphocytes of CHD patients produced significantly more IL-2 and IL-4 than those from HV, suggesting an activation of their T lymphocytes. We conclude that using the cytokine flow cytometry assay, our study demonstrated that in HCV(+) CHD patients, as opposed to what has been described for HCV(+) patients with normal renal function, there was no impairment in the production of type 1 cytokines by peripheral blood mononuclear cells when compared to HCV(-) CHD patients. Conversely to HV, T lymphocytes from CHD patients are activated.     

Characterization of Virus-Specific T-Cell Immunity in Liver Allograft Recipients with HCV-Induced Cirrhosis

Recurrent hepatitis C infection (HCV) following liver transplantation causes accelerated allograft cirrhosis. Here we characterized HCV-specific immunity in adult liver transplant recipients (n = 74) with and without allograft cirrhosis. Patients were divided into hepatic inflammation/no cirrhosis (METAVIR scores 0–2, HIN) and hepatic cirrhosis (score 3–4, HFC). As control, 20 normal subjects and 10 non-HCV liver transplant patients were included. Twenty-five different serum cytokines were analyzed using LUMINEX. Frequency of T-cells specific to HCV-derived proteins (NS3, NS4, NS5, Core) was characterized using ELISPOT immunoassays. There was no difference in clinical characteristics between HIN (n = 49) and HFC (n = 25) groups. HIN group had high serum IFN-γ and IL-12 while HFC demonstrated elevated IL-4, IL-5 and IL-10 (p < 0.01). HCV (NS3, NS4, NS5, Core)-specific IFN-γ-producing CD4⁺ T-cells were elevated in the HIN group whereas the HFC patients showed predominance of HCV-specific IL-5 and IL-10-producing CD4⁺ T-cells. Conclusions : Lack of HCV-specific Th1-type T-cell immunity is observed in liver transplant recipients with advanced allograft cirrhosis.     

Pretransplantation CD56(+) innate lymphocyte populations associated with severity of hepatitis C virus recurrence.

Cluster of differentiation (CD)56(+) lymphocytes are believed to play important roles in the innate immune response to viral infections by production of interferon (IFN)-gamma and/or the recognition of virally infected cells, but their role in liver transplantation (LT) has not been characterized. Here, for the first time, we examine the phenotypic and functional features of these cells in patients undergoing LT for hepatitis C virus (HCV)-related liver failure. The study was comprised of four patient groups: patients with mild HCV recurrence (n = 9), severe HCV recurrence (n = 10), patients with non-HCV-related liver failure (n =10), and normal healthy subjects (n = 10). Pre-LT, the frequency of circulating CD56(+) lymphocytes was significantly lower in patients who subsequently developed severe HCV recurrence, relative to those patients who developed mild histologic recurrence, as well as non-HCV controls. HCV was associated with impaired lymphokine-activated killing and natural cytotoxicity. We found that natural T (NT) cells that coexpressed CD4/CD8 or expressed CD8 alone were more frequent in patients who subsequently developed severe recurrence. In contrast, NT cells that expressed only CD4 appeared to be depleted in HCV infection relative to controls. A significantly higher percentage of NTs in both HCV groups expressed the inhibitory receptor NKG2A relative to HCV-negative controls with liver disease. In conclusion, these results demonstrate a previously unappreciated association between pretransplantation CD56(+) lymphocytes and outcome of HCV recurrence and provide novel mechanistic insights into the immunopathogenesis of HCV recurrence, as well as potential targets for therapeutic manipulation.     

Cytokine profile of liver- and blood-derived nonspecific T cells after liver transplantation: T helper cells type 1/0 lymphokines dominate in recurrent hepatitis C virus infection and rejection

Orthotopic liver transplantation (OLT) is a successfultreatment in patients with hepatitis C virus (HCV)-associated end-stage liver disease worldwide. T lymphocytes and their cytokines are believed to have a pivotal role in the defense against HCV and in allograft rejection. An immunosuppressive drug regimen may cause a cytokine imbalance toward a T helper (TH) cell type 2 profile that is associated with the persistence of infection and acceptance of the graft. The aim of this study is to assess whether cytokine imbalances toward a TH 1- or TH2-type response may have a role in recurrent HCV infection and rejection after OLT Twenty-one intrahepatic Tcell lines of 15 patients with recurrent HCV infection after OLT (group A) and 15 lines of 11 patients with rejection (group B) were studied. Both patient groups had received liver allografts because of HCV-associated end-stage liver disease. Patients with HCV-induced liver disease who did not undergo OLT served as controls: 17 patients with chronic hepatitis C (CH-C) and 8 patients with cirrhosis. At the time of liver biopsy, 14 blood-derived Tcell lines of 12 patients with recurrent HCV infection, 7 of 10 patients with rejection, and 18 of 18 control patients were also investigated. Regardless of the underlying disease (recurrent HCV infection, rejection, HCVinduced hepatitis, and cirrhosis), all liver tissue-derived Tcell lines produced interferon-'Y; some additionally produced interleukin-4 (IL-4), but none produced IL-10, indicating that the TH0/1 cytokine profile dominates. Tcell lines showing a TH1 cytokine profile derived from intrahepatic T cells could be established significantly more often in recurrent HCV infection and rejection than in controls with CH-C (Fisher's exact test, P < .05). The cytokine profile of intrahepatic T cells did not differ from that obtained in peripheral blood. TH0/1 cytokine profile dominates the intrahepatic and blood-derived immune response in recurrent HCV infection and rejection after OLT regardless of the mode of immunosuppressvn. The lymphokine profile of immunocompromised patients with recurrent HCV infection or rejection does not differ principally from that of patients with HCV-induced hepatitis and cirrhosis, but seems to show a TH1 profile significantly more often.     

Regulatory effect of FK506 on CD152 and PD-1 in the liver allorecipients

AIM: We dynamically observed the expression of CD152 and PD-1 on T-cell surfaces in peripheral blood of liver allorecipients to explore the regulatory effect of FK506 on negative costimulatory molecules. METHODS: We evaluated 20 liver allorecipients, 19 end-stage liver disease patients, and 20 healthy volunteers for FK506 concentrations measured by an enzyme-multiplied immunoassay technique and flow cytometry to determine T-cell subsets as well as CD152 and PD-1 expression. RESULTS: After liver transplantation, the frequency of CD4+ T cells gradually decreased to significantly lower level than those in the disease controls (P < .05). CD8+ T cells in each treatment group were obviously higher than those in the disease controls (P < .05). The expression of CD152 on CD4+ and CD8+ T cells was greater than those in healthy controls (P < .05); and at 2 and 4 weeks, higher than those in disease controls (P < .05). The expression of PD-1 on CD4+ T cells from the 2 weeks after treatment was significantly greater than that in healthy controls (P < .05), and that on CD8+ T cells increased obviously from the 4 weeks compared with disease controls (P < .05). CONCLUSION: FK506 up-regulated the expression of CD152 and PD-1 on the T-cell surface inhibiting proliferation and activation of effector T cells, favoring the survival of allorecipients.     

Tacrolimus and cyclosporin doses and blood levels in hepatitis C and alcoholic liver disease patients after liver transplantation.

Hepatitis C virus (HCV)-induced cirrhosis is the most common indication for liver transplantation (LT). However, graft reinfection is nearly universal. The choice of immunosuppression, including the calcineurin inhibitor (CNI), may have some effect on severity of recurrence and graft survival. In addition, HCV recurrence may have some impact on metabolism of immunosuppressive drugs. In this retrospective study, we examined the dose and blood levels of tacrolimus (TAC) and cyclosporin A (CYA) in HCV patients consecutively undergoing transplantation (TAC, n = 44; CYA, n = 60) and surviving 12 months post-LT. In addition, we examined the CNI dose and blood levels in an age- and gender-matched comparison group of patients who were transplanted for alcoholic liver disease (ALD) (TAC, n = 44; CYA, n = 47). During the 12-month period of observation, TAC levels were significantly higher for HCV than for ALD patients (P = 0.002). The dose of TAC decreased over time for both HCV and ALD patients (P < 0.001), but the reduction was greater for HCV patients (P = 0.03). CYA dose decreased over time for both groups (P < 0.001) but a greater reduction was observed for the HCV group (P = 0.007). For both HCV and ALD patients, CYA levels decreased over time (P < 0.001) but there was no significant difference between HCV and ALD patients. Thus, to maintain comparable blood levels, a greater reduction of dose was required for HCV than for ALD patients. In conclusion, our observations demonstrate a likely effect of HCV infection on CNI metabolism, an effect that is not clearly due to graft damage. Physicians need to be alert to this interaction and to the need to respond quickly to changes in CNI levels that may be associated with HCV infection and with HCV clearance during antiviral therapy.     

Transplantation for alcoholic cirrhosis: How does recurrence of disease harm the graft?

Abstract Many transplant centres are reluctant to accept alcoholic patients because of their supposed potential for alcoholic recidivism, resulting in graft failure and recurrence of alcoholic liver cirrhosis. From May 1982 to January 1993 80 patients received orthotopic liver transplantation (OLT) at our institution either for alcoholic cirrhosis exclusively ( n = 58) or for a hepatoma in an alcoholic cirrhosis ( n = 22). The outcome of these patients was analysed with particular attention to recurrence of liver disease. Overall survival in this group was 67% and 49% at 1 and 5 years, respectively, with a median follow-up' of 45 months. Actuarial survival of patients transplanted since January 1989 ( n = 46) and 84% and 82% at 1 and 2 years (median follow-up 31 months). Non-fatal clinical endpoints were analysed in those patients surviving for at least 3 months ( n = 61). Return to alcohol abuse was documented in 16 patients at routine short-term out patient check-ups. All patients except one admitted to taking alcohol and showed changes in their laboratory test results. A specific pattern of liver function test values related to alcohol abuse was not detected and at the end of a relapse the liver function values usually returned to pre-event values. Only in one case was toxic injury of the liver related to alcoholic recidivism diagnosed on percutaneous liver needle biopsy or post-mortem examination. Com-plicance with the required immunosuppressive regimen and social rehabilitation after OLT were excellent. Unwillingness to offer OLT to individuals with alcoholic liver disease because of failure to demonstrate 100% long-term abstinence appears difficult to defend in the face of results showing good survival, compliance and social rehabilittion. The hypothesis of a higher sensitivity of the transplanted liver to a drinking episode and the redevelopment of alcoholic diesease in the new liver was not confirmed in our study population.     

Diabetes mellitus after liver transplant new etiologic clues and cornerstones for understanding

A retrospective study was performed on all orthotopic liver transplant (OLT) recipients (n = 167) from a major French transplant center from January 1998 to December 2000. The investigation sought to determine the prevalence, predictive factors, and outcome of post-liver transplant diabetes mellitus (PTDM). PTDM was defined at 6 months post-OLT as hyperglycemia requiring treatment with insulin or oral hypoglycemic agents. The incidence was assessed for patient features, cause of liver disease, and immunosuppressive regimen. PTDM occurred in 45 of 143 OLT (31%), including 27 patients with pre-OLT persistent DM, whereas 26 developed de novo PTDM. Eight patients were cured of their post-OLT DM. PTDM treatment consisted of mainly insulin (n = 43). Patients given tacrolimus (n = 40) had a greater incidence of PTDM. Pre-OLT DM (n = 27), alcoholic cirrhosis (n = 30), and male gender (n = 38) were independent predictors of PTDM. Recipient HLA, steroid dosage, hepatitis C virus (HCV), and cholestatic liver disease were not predictive of PTDM. The incidences of graft loss as well as other morbidities and death rates were similar between the two groups. In conclusion, PTDM, common occurrence associated with male gender, alcoholic cirrhosis, and pre-OLT DM, seems at midterm follow-up to have no pejorative evolution when compared to patients without this complication.     

Role of bcl-2 mRNA in homeostatic proliferation in circulating T-cells in human liver transplant patients after T-cell depletion

BACKGROUND: Prolonged T-cell depletion after liver transplantation leads to life-threatening infections. Members of the anti-apoptotic Bcl-2 gene family can maintain T-cell viability. T-cell numbers and their Bcl-2 expression following living donor liver transplantation (LDLT) were analyzed in 108 surviving and 13 deceased recipients. MATERIALS AND METHODS: Bcl-2 mRNA levels and phenotypic changes of T-cells were examined by quantitative PCR and by measuring expression of CD45RO and CCR7. RESULTS: Based on the restoration of peripheral T-cell numbers, the 108 surviving recipients were classified into three groups. All recipients showed T-cell depletion, down to approximately 30% of pretransplant levels within 3 h of graft reperfusion. In Group I, the T-cell numbers were rapidly restored to pretransplant levels, within 5 days, with a rapid decrease in Bcl-2 mRNA levels immediately after LDLT. In Group II, the T-cell numbers were restored to normal levels by 19 days, with down-regulation of Bcl-2 mRNA. In Group III, the T-cell numbers were maintained at low levels for much longer, with high levels of Bcl-2 mRNA. In all three groups of recipients, there was statistically significant (r = -0.78) inverse correlation between T-cell numbers and Bcl-2 mRNA. CONCLUSIONS: For successful transplantation, homeostatic restoration of T-cells must occur as soon as possible. Evaluation of peripheral T-cell numbers and of Bcl-2 expression may have therapeutic potential in identifying those transplant patients who face increased risk of infection.     

Liver transplant waitlist outcomes in alcoholic hepatitis compared with other liver diseases: An analysis of UNOS registry

There is growing interest in performing liver transplantation (LT) in patients with alcoholic hepatitis (AH) without a mandated abstinence period. The aim of this study is to investigate waitlist outcomes in AH patients compared to those with other liver diseases. Using data from the UNOS registry, adult patients listed for LT between 2009 and 2018 were evaluated. Waitlist outcomes were compared among liver diseases. A total of 64 646 patients were eligible, including 286 with AH, 16 871 with alcoholic cirrhosis (AC), 13 730 with hepatitis C (HCV), 10 315 with non-alcoholic steatohepatitis (NASH), and 5841 with cholestatic liver disease (CLD). In comparison with AH patients, patients with HCV, NASH, and CLD had a significantly higher risk of waitlist mortality and a lower likelihood of recovery on the waitlist. These trends were more prominent in the waiting-time period of 91-365 days than in shorter periods. In intention-to-treat analysis, positive prognostic effect of LT was significant in AH patients with MELD score ≥35 (HR 0.04, P < .001). AH patients showed lower mortality risk and a higher chance of recovery while on waitlist than other liver diseases, especially when waiting time exceeded 90 days. These results indicate the importance of continuous evaluation of disease progression in AH patients awaiting LT.     

Hepatocellular carcinoma in HCV-infected patients awaiting liver transplantation: genes involved in tumor progression.

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer death in the world. The present study aimed to investigate the genes involved in viral carcinogenesis and tumor progression in liver transplant recipients with hepatitis C virus (HCV) and HCC. To accomplish this, we performed the analysis of hepatic gene expression in HCV-infected liver recipient patients with stages of disease ranging from early cirrhosis with preserved volume and function to late cirrhosis with diminished volume and function with and without HCC. We found consistent differences between the gene expression patterns in HCV-HCC and those of early HCV-cirrhosis, late HCV cirrhosis, and normal control livers. The expression patterns in HCC were also readily distinguished between early and advanced HCC tumor stages. Moreover, we found different gene expression patterns between early cirrhosis and late cirrhosis. In conclusion, these findings confirm the presence of multiple molecular alterations during HCV-HCC hepatocarcinogenesis and, clinically, indicate the possibility for identifying prognostic factors associated with HCC progression in liver transplant patients waiting for a donor and/or posttransplantation recurrence.     

Impact of hepatitis C virus infection on patient and graft survival in kidney transplantation

Hepatitis C virus (HCV) infection is the main cause of chronic liver disease after renal transplantation, which represents a risk factor for graft loss and patient death. Hepatitis C (+) kidney transplant candidates who remain on the waiting list show a greater risk of mortality than those who are transplanted, a risk that escalates with time. The aim of this study was to examine the impact of HCV infection on patient and allograft survival in our transplant population. Among 90 renal transplant patients transplanted between 1991 and 2002 who were retrospectively analyzed, 45 were HCV-positive and 45 HCV-negative by serology. All positive patients had shown positive HCV antibody and/or positive HCV RNA. The mean ages of the patients were 36.2 +/- 9 years among the HCV (+) and 38 +/- 10 years among the HCV (-) patients (P = .31). Eighteen HCV (+) patients and 14 HCV (-) patients received their grafts from deceased donors. The immunosuppressive protocols were similar in both groups. The number of acute rejection episodes were 13 (30%) in HCV (+) and 6 (13%) in the HCV (-) group (P = .006). Diabetes mellitus developed in 10 (23%) HCV (+) and 7 (16%) HCV (-) patients (P = .04). Cytomegalovirus disease occurred in 5 (16%) HCV (+) and 2 (6%) HCV (-) patients (P = .32). The mean serum creatinine was 1.85 +/- 1.1 mg/dL in HCV (+) and 1.8 +/- 1 mg/dL in HCV (-) group (P = .82). The mean graft survivals were 97.1 +/- 52 months in the HCV (+) and 81.1 +/- 37 months in the HCV (-) group (P = .04). Seven HCV (+) patients (16%) and three HCV (-) patients (6%) lost their grafts (P = .04). Advanced cirrhosis developed in three HCV (+) patients (6%). One patient died in the HCV (+) group. Patient survivals were 98% in the HCV (+) and 100% in the HCV (-) cohorts. In this study, the rate of graft loss was higher in HCV (+) patients, whereas the patient survival was similar.     

Severe recurrent hepatitis C after liver retransplantation for hepatitis C virus–related graft cirrhosis

An increase in the number of hepatitis C virus (HCV)-infected transplant recipients at need for repeated liver transplantation is anticipated. To date, there is a certain reluctance to accept these patients because of an increased organ shortage, early reports suggesting a poor outcome, and uncertainty regarding the natural history of recurrent hepatitis C in the second graft. The aim of this study is to determine the outcome of patients undergoing retransplantation for HCV-related graft cirrhosis. Of 49 transplant recipients with HCV-related allograft cirrhosis, 31 patients developed decompensation with criteria for retransplantation. Thirteen patients were denied this option. Of the 18 patients accepted, 6 patients died while on the waiting list (5 patients died of graft cirrhosis at a median of 3.2 months of listing), and 12 patients have undergone retransplantation (median, 10 months since HCV cirrhosis). After retransplantation, 8 patients (67%) died at a median of 8 months, and 4 patients (33%) remain alive after 1.9 years of follow-up. Causes and times of death from retransplantation were: surgical complications, n = 3 (perioperative period); HCV cirrhosis of the second graft, n = 2 (at 9 and 54 months); fibrosing cholestatic hepatitis, n = 1 (at 2 years); lymphoproliferative disorder, n = 1 (at 7 months); and endocarditis, n = 1 (at 3.5 years, with underlying cirrhosis). Of the 4 patients alive, fibrosis stages in the last biopsy specimens are stage 1 (n = 1), stage 3 (n = 1), and stage 4 or cirrhosis (n = 1; one patient has not undergone biopsy), despite antiviral therapy. The outcome of retransplantation for HCV cirrhosis of the first graft is very poor because of multiple complications. The severity of recurrent HCV disease in the second graft seems to be related to that observed in the first graft. (Liver Transpl 2003;9:228-235.)     

Femur fracture induces site-specific changes in T-cell immunity

BACKGROUND. Trauma is associated with altered host defense and susceptibility to infection, in part due to cytokine dysregulation and altered T-cell immunity. The gut-associated lymphoid tissue (GALT) provides a defense against infection and contributes to the process of mucosal healing by T-cell activation and cytokine production. OBJECTIVE. To determine whether femur fracture induces alterations in Peyer's patch and splenic T-cell phenotype, proliferative response, and cytokine expression following traumatic injury. METHODS. Mice underwent femur fracture or sham procedure and, 48 h later, lymphocytes were isolated from spleen and Peyer's patches. Lymphocytes were cultured, and lipopolysaccharide (10 microg/ml) was added in some cultures. Cells and supernatant were harvested at 48 h. Proliferation was analyzed by [3H]thymidine, and interleukin-10 (IL-10) protein was measured by ELISA in the culture supernatant. T-cell phenotype was determined by flow cytometry. RESULTS. Femur fracture induced a significant increase in proliferative response in Peyer's patch immunocytes. In contrast, no significant differences were identified in splenocyte proliferative response 48 h after femur fracture injury. Femur fracture induced a significant decrease in IL-10 protein expression of both splenocytes and Peyer's patches. Femur fracture also induced a significant increase in the fraction of CD3(+), CD4(+), and T-cell receptor-alpha beta Peyer's patch immunocytes, whereas splenocytes demonstrated no significant phenotypic change. CONCLUSION. Femur fracture is associated with significant alterations in Peyer's patch but not splenic T-cell phenotype and proliferative response early (48 h) after injury. Changes in the GALT immune response may contribute to intestinal mucosal dysfunction and increased susceptibility to gut-derived sepsis after traumatic injury.     

Primary biliary cirrhosis has high wait‐list mortality among patients listed for liver transplantation

Patients with primary sclerosing cholangitis (PSC) have frequent episodes of cholangitis with potential for high mortality while waiting for liver transplantation. However, data on wait‐list mortality specific to liver disease etiology are limited. Using United Network for Organ Sharing (UNOS) database (2002–2013), of 81 592 listed patients, 11 284 (13.8%) died while waiting for transplant. Primary biliary cirrhosis (PBC) patients (N = 3491) compared to PSC (N = 4905) differed with age (56 vs. 47 years), female gender (88% vs. 33%), black race (6% vs. 13%), and BMI (25 vs. 27), P < 0.0001 for all. A total of 993 (11.8%) patients died while waiting for the transplant list. Using competing risk analysis controlling for baseline recipient factors and accounting for receipt of liver transplantation (LT), PBC compared to patients with PSC had higher overall and 3‐month wait‐list mortality (21.6% vs. 12.7% and 5.0% vs. 2.9%, respectively, Gray's test P < 0.001), [1.25 (1.07–1.47)]. Repeat analysis including all etiologies showed higher wait‐list mortality for PBC compared to most etiologies, except for patients listed for diagnosis of alcoholic liver disease (ALD) + hepatitis C virus (HCV). Patients with PBC have high mortality while waiting for liver transplantation. These novel findings suggest that patients with PBC listed for LT may be considered for model for end‐stage disease (MELD) exception points.     

Progression of liver fibrosis in patients with chronic hepatitis C after orthotopic liver transplantation

BACKGROUND: Hepatitis C virus (HCV)-related cirrhosis is the leading indication for orthotopic liver transplantation (OLTx). HCV recurrence is universal after OLTx, with a highly variable course. This study aimed to find factors that affect progression of fibrosis in recurrent HCV. METHODS: Fifty-eight HCV patients underwent OLTx at our center who were selected on the basis of available preOLTx serum or explanted liver sample and liver biopsy obtained at least 6 months postOLTx. All liver biopsies were performed when clinically indicated and were scored using the modified Hepatitis Activity Index (HAI). Primary immunosuppression consisted of tacrolimus and prednisone. RESULTS: The group included 41 males (mean age 49.6 years). HCV genotype distribution was 1a, 31 (53%); 1b, 16 (28%), and others 11 (19%). The mean follow-up was 53.1 months. Patients with genotype 1a (n=31; mean 46.3 months) had significantly lower fibrosis-free survival analyzed by the presence of fibrosis stages 5 and 6 when compared with other genotypes (n=27; mean 60.1 months; P=0.0088, log rank test). Mean HAI scores were significantly higher in HCV genotype 1a, although there were no differences in survival between genotypes. Similarly, patients with cytomegalovirus (CMV) infection postOLTx (n=4) had a higher fibrosis progression rate compared with those without CMV (n=54) (mean fibrosis-free survival 29.0 vs. 53.0 months P=0.0004, log-rank test). Human leukocyte antigen matching and rate of acute rejection did not influence progression of fibrosis. CONCLUSION: Patients with HCV genotype 1a and those developing CMV postOLTx have a higher rate of hepatic fibrosis progression after OLTx for HCV-related chronic liver disease.     

Chances and limitations of non‐invasive tests in the assessment of liver fibrosis in liver transplant patients

Kamphues C, Lotz K, Röcken C, Berg T, Eurich D, Pratschke J, Neuhaus P, Neumann UP. Chances and limitations of non‐invasive tests in the assessment of liver fibrosis in liver transplant patients.
Clin Transplant 2009 DOI:10.1111/j.1399‐0012.2009.01152.x
© 2009 John Wiley & Sons A/S. Abstract: Because fibrosis progression resulting in liver cirrhosis represents the main reason for graft lost in patients after liver transplantation, an early detection of liver fibrosis is crucial. In recent years, several non‐invasive tests for the assessment of liver fibrosis have been developed. We prospectively assessed the stage of liver fibrosis of 135 liver transplant patients (94 hepatitis C virus [HCV], 41 alcoholic cirrhosis) using liver biopsy, transient elastography, and serum markers. In the HCV group, the area under the receiver operating characteristic curve (AUROC) for diagnosis of significant fibrosis (F ≥ 2) and cirrhosis (F = 4) was 0.81 (negative predictive value [NPV] = 0.58, positive predictive value [PPV] = 0.9) and 0.87 (NPV = 0.94, PPV = 0.56), respectively. In the alcoholic cirrhosis group, significant fibrosis (F ≥ 2) was diagnosed with an AUROC of 0.83 (NPV = 1.00, PPV = 0.23). In both groups, higher AUROC values were reached in patients with a body mass index of <25 kg/m², and both serum markers showed no significant correlation to liver fibrosis. The transient elastography is a reliable test for exclusion of liver cirrhosis in HCV transplant and significant liver fibrosis in alcoholic transplant patients. For the diagnosis of significant liver fibrosis in HCV transplant patients, the transient elastography reaches good results but cannot replace liver biopsy. Both serum markers AST‐to‐platelet ratio index and FIB‐4 are not feasible to assess liver fibrosis in liver transplant patients.