Falk Rauchfuß

Impact of stable PGI2 analog iloprost on early graft viability after liver transplantation: a pilot study

Bärthel E, Rauchfuß F, Hoyer H, Habrecht O, Jandt K, Götz M, Voigt R, Heise M, Marx G, Settmacher U. Impact of stable PGI2 analog iloprost on early graft viability after liver transplantation: a pilot study. 
Clin Transplant 2012: 26: E38–E47. 
© 2011 John Wiley & Sons A/S.

The PRAISE study: a prospective, multi-center, randomized, double blinded, placebo-controlled study for the evaluation of iloprost in the early postoperative period after liver transplantation (ISRCTN12622749).

BackgroundLiver graft dysfunction can deteriorate to complete organ failure and increases perioperative morbidity and mortality after liver transplantation. Therapeutic strategies reducing the rate of graft dysfunction are of current clinical relevance. One approach is the systemic application of prostaglandins, which were demonstrated to be beneficial in reducing ischemia-reperfusion injury. Preliminary data indicate a positive effect of prostacyclin analogue iloprost on allograft viability after liver transplantation. The objective of the study is to evaluate the impact of iloprost in a multi-center trial.Methods/DesignA prospective, double-blinded, randomized, placebo-controlled multicenter study in a total of 365 liver transplant recipients was designed to assess the effect of intravenous iloprost after liver transplantation. Primary endpoint will be the primary graft dysfunction characterized as presentation of one or more of the following criteria: ALAT or ASAT level > 2000 IU/ml within the first 7 postoperative days, bilirubine ≥ 10 mg/dl on postoperative day 7; INR ≥ 1.6 on postoperative day 7 or initial non-function. Secondary endpoints are parameters of post-transplant morbidity, like rates of infections, biliary complications, need of clotting factors or renal replacement therapy and the graft and patient survival.DiscussionA well-established treatment concept to avoid graft dysfunction after liver transplantation does not exist at the moment. If the data of this research project confirm prior findings, iloprost would improve the general outcome after liver transplantation.Trial RegistrationGerman Clinical Trials Register: DRKS00003514. Current Controlled Trials Register: ISRCTN12622749.

Chemerin in peritoneal sepsis and its associations with glucose metabolism and prognosis: a translational cross-sectional study

BackgroundStress hyperglycaemia (SHG) is a common complication in sepsis associated with poor outcome. Chemerin is an adipocytokine associated with inflammation and impaired glucose homeostasis in metabolic diseases such as type 2 diabetes (T2D). We aimed to investigate how alterations of circulating chemerin levels and corresponding visceral adipose tissue (VAT) expression are linked to glucose metabolism and prognosis in sepsis.MethodsClinical data and tissue samples were taken from a cross-sectional study including control, T2D and sepsis patients, all undergoing laparotomy. A second independent patient cohort of patients with sepsis was included to evaluate associations with prognosis. This was complemented by a murine model of peritoneal infection and a high-fat diet. We analysed circulating chemerin by enzyme-linked immunosorbent assay and VAT messenger RNA (mRNA) expression by real-time polymerase chain reaction.ResultsCirculating chemerin was increased in sepsis 1.69-fold compared with controls (p = 0.012) and 1.47-fold compared with T2D (p = 0.03). Otherwise, chemerin VAT mRNA expression was decreased in patients with sepsis (p = 0.006) and in septic diabetic animals (p = 0.009). Circulating chemerin correlated significantly with intra-operative glucose (r = 0.662; p = 0.01) and in trend with fasting glucose (r = 0.528; p = 0.052). After adjusting for body mass index or haemoglobin A1c, chemerin correlated in trend with insulin resistance evaluated using the logarithmised homeostasis model assessment of insulin resistance (r = 0.539, p = 0.071; r = 0.553, p = 0.062). Chemerin was positively associated with Acute Physiology and Chronic Health Evaluation II score in patients with sepsis (p = 0.036) and with clinical severity in septic mice (p = 0.031). In an independent study population, we confirmed association of chemerin with glucose levels in multivariate linear regression analysis (β = 0.556, p = 0.013). In patients with sepsis with SHG, non-survivors had significantly lower chemerin levels than survivors (0.38-fold, p = 0.006), while in patients without SHG, non-survivors had higher chemerin levels, not reaching significance (1.64-fold, p = 0.089). No difference was apparent in patients with pre-existing T2D (p = 0.44).ConclusionsWe show, for the first time to our knowledge, that chemerin is increased in sepsis and that it associates with impaired glucose metabolism and survival in these patients. It could be further evaluated as a biomarker to stratify mortality risk of patients with SHG.

Liver transplantation for hepatocellular carcinoma - factors influencing outcome and disease-free survival.

Hepatocellular carcinoma is one of the leading causes of cancer-related death worldwide. Liver transplantation can be a curative treatment in selected patients. However, there are several factors that influence disease-free survival after transplantation. This review addresses the pre-, intra- and postoperative factors that influence the risk of tumor recurrence after liver transplantation.

Fetuin A is a Predictor of Liver Fat in Preoperative Patients with Nonalcoholic Fatty Liver Disease

ABSTRACT Background: Nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are frequent comorbidities in perioperative patients. However, the predictive role of the hepatokine fetuin A was not evaluated in this collective. Objective: To study fetuin A as predictor of NAFLD/NASH in preoperative patients. Methods: 58 subjects were included. Fetuin A was studied in patients undergoing open abdominal surgery and in a subset with acute liver failure. Blood and liver specimens were sampled. NAFLD was histologically evaluated. Liver fat was additionally analyzed by an enzymatic approach, circulating fetuin A by enzyme linked-immunosorbent assay, fetuin A mRNA by reverse-transcription PCR. Results: Univariate correlation studies linked fetuin A to liver steatosis (r = 0.40, p = .029) and hepatocellular ballooning degeneration (r = 0.34, p = .026). Compared to non-NAFLD subjects fetuin A was increased in NAFLD (p = .009) and in NASH (p = .029). However, when corrected for main confounders by linear modeling, fetuin A remained related to hepatic steatosis, but not to ballooning degeneration or other NAFLD features. In support of this, biochemically analyzed liver lipids correlated with fetuin A in plasma (r = 0.34, p = .033) and with hepatic fetuin A mRNA (r = 0.54, p < .001). In addition, plasma fetuin A was related to hepatic mRNA (r = 0.32, p = .036), while circulating levels were reduced by 64% with acute liver failure (p < .001), confirming the liver as main fetuin A source. Conclusion: Fetuin A is suggested as noninvasive biomarker of hepatic steatosis in preoperative settings.

Prostaglandin application improves macro- and microcirculation after aorto-hepato-mesenteric bypass in chronic mesenteric ischemia

Chronic mesenterial ischemia (CMI) is an uncommon cause of abdominal afflictions. The spectrum of therapeutic options ranges from mesenteric artery angioplasty and stenting to surgical revascularization. We used orthogonal polarization spectral (OPS) imaging to assess microcirculation after revascularization of the celiac artery and the superior mesenteric artery. Furthermore, we applicated a prostaglandin I2 derivate (iloprost, Ilomedin®, BayerVital GmbH, Leverkusen, Germany) after bypass reperfusion and demonstrated the effect of this vasodilatative agent to microcirculatory parameters. Our patient was a 52-year-old woman who suffered from a complete obstruction of the celiac artery as well as high-grade stenosis of the superior mesenteric artery (SMA). Therefore, we performed an open revascularization using the greater saphenous vein of the left thigh as graft (reversed vein bypass from the supraceliac aorta sequentially to the celiac artery (termino-lateral anastomosis) and the superior mesenteric artery (termino-terminal anastomosis)). After bypass reperfusion, we administered 3 μg iloprost as bolus directly into the bypass. The agreement of the patient was obtained before the aforementioned procedure and the measurements. Immediately following laparotomy, bypass reperfusion and iloprost administration, we measured the microcirculation of stomach, pancreas, small intestine and right hemi-colon. Microhemodynamic analysis included the quantitative analysis of capillary diameter (D), functional capillary density (FCD) and red blood cell velocity (RBCV). Using these parameters, we calculated the individual capillary volumetric flow rate (capillary blood flow (CBF); in picoliter/s; pl/s) and the perfusion index (PI).

Induction of chronic cholestasis without liver cirrhosis - Creation of an animal model

AIM To analyze time intervals of inflammation and regeneration in a cholestatic rat liver model. METHODS In 36 Lewis rats, divided into six groups of 6 animals (postoperative observation periods: 1, 2, 3, 4, 6, 8 wk), the main bile duct was ligated with two ligatures and observed for the periods mentioned above. For laboratory evaluation, cholestasis parameters (bilirubin, γ-GT), liver cell parameters (ASAT, ALAT) and liver synthesis parameters (quick, albumin) were determined. For histological analysis, HE, EvG, ASDCL and HMGB-1 stainings were performed. Furthermore, we used the mRNA of IL-33, GADD45a and p-21 for analyzing cellular stress and regeneration in cholestatic rats. RESULTS In chemical laboratory and histological evaluation, a distinction between acute and chronic cholestatic liver injury with identification of inflammation and regeneration could be demonstrated by an increase in cholestasis (bilirubin: 1-wk group, 156.83 ± 34.12 μmol/L, P = 0.004) and liver cell parameters (ASAT: 2-wk group, 2.1 ± 2.19 μmol/L.s, P = 0.03; ALAT: 2-wk group, 1.03 ± 0.38 μmol/L.s, P = 0.03) after bile duct ligation (BDL). Histological evaluation showed an increase of bile ducts per portal field (3-wk group, 48 ± 6.13, P = 0.004) during the first four weeks after bile duct ligation. In addition to inflammation, which is an expression of acute cholestasis, there was an increase of necrotic areas in the histological sections (2-wk group, 1.38% ± 2.28% per slide, P = 0.002). Furthermore, the inflammation could be verified by ASDCL (4-wk group, 22 ± 5.93 positive cells per portal field, P = 0.041) and HMGB-1 [2-wk group, 13 ± 8.18 positive cells per field of view (FoV), P = 0.065] staining. Therefore, in summary of the laboratory evaluation and histological studies, acute cholestasis could be found during the first four weeks after bile duct ligation. Subsequently, the described parameters declined so that chronic cholestasis could be assumed. For quantification of secondary biliary cirrhosis, eosin staining was performed, which did not reveal any signs of liver remodeling, thus precluding the development of a chronic cholestasis model. Additionally, to establish the chronic cholestasis model, we evaluated liver regeneration capacity through measurements of IL-33, p-21 and GADD45a mRNA. CONCLUSION We created a chronic cholestasis model. The point of inflammatory and regenerative balance was reached after four weeks. This finding should be used for experimental approaches dealing with chronic cholestatic liver damage.

Searching the ideal hepatocellular carcinoma patient for liver transplantation: are the Toronto criteria a step in the right direction?

Since the introduction of Milan criteria by Mazzaferro et al. in 1996 (1), many transplant programs and allocation systems use these criteria for the selection of suitable candidates for liver transplantation in hepatocellular carcinoma (HCC) patients.

Bowel Ischemia in ICU Patients: Diagnostic Value of I-FABP Depends on the Interval to the Triggering Event

Background Intestinal fatty acid-binding protein (I-FABP) has been shown to be of high diagnostic value in patients with acute mesenteric ischemia. Whether these results can be reproduced in critically ill patients on the ICU was to be investigated. Materials and Methods I-FABP was measured in serum and urine of 43 critically ill patients in ICU when mesenteric ischemia was suspected. Bowel ischemia was confirmed in 21 patients (group 1). 22 patients who survived at least seven days without confirmation of ischemia were assigned to group 2. I-FABP levels were compared between the groups, and interval from the event that has triggered ischemia to I-FABP measurement was recorded. Results For the identification of patients with mesenteric ischemia, sensitivity, specificity, and area under the curve (AUC) for serum and urine I-FABP were 33.3%, 95.5%, and 0.565 and 81.3%, 70.0%, and 0.694, respectively. I-FABP measurements performed within 12 to 48 h after the event that triggered ischemia showed a sensitivity, specificity, and AUC for serum and urine of 75%, 100%, and 0.853 and 100%, 73.3%, and 0.856, respectively. Conclusions In ICU patients, one single I-FABP measurement at the time of clinical suspicion failed to reliably detect or exclude mesenteric ischemia. A higher diagnostic value of I-FABP was only confirmed in the early stages of mesenteric ischemia. I-FABP may be used most appropriately in perioperative monitoring.

Additional file 3: of Chemerin in peritoneal sepsis and its associations with glucose metabolism and prognosis: a translational cross-sectional study

Figure S2. Correlation of fasting and intra-operative glucose levels with circulating chemerin in controls. a Correlation of circulating chemerin levels with fasting glucose levels (r = 0.216, p = 0.034, n = 17). b Correlation of circulating chemerin levels with OP glucose (r = 0.549, p = 0.023, n = 17). (PDF 44 kb)