Jan Bruensing

Background & Aims: Acute liver failure (ALF) is a life‐threatening condition with a high mortality rate. The expression of urokinase plasminogen activator receptor (uPAR, CD87) and release of its shedded receptor into serum as soluble uPAR (suPAR) have been closely related to immune activation and prognosis in systemic inflammation and cirrhosis. We now aimed at investigating the clinical relevance and cellular source of uPAR and circulating suPAR in ALF.Methods: Serum suPAR concentrations were measured in 48 ALF patients and 62 healthy controls from a German liver transplantation centre. Hepatic immune cell subsets and uPAR expression were studied by FACS, qPCR and immunohistochemistry.Results: Circulating suPAR levels were significantly increased in ALF patients, independent from the underlying aetiology, in comparison to controls. Serum suPAR concentrations were closely correlated with parameters reflecting liver cell injury, decreased liver function and the model of end‐stage liver disease (MELD) score inALFpatients. By immunohistochemistry from explanted livers,ALFwas associated with distinct immune cell accumulation and strong up‐regulation of intrahepatic uPAR mRNA expression. CD87 (uPAR) expression was specifically detected on intrahepatic ‘non‐classical’ monocytes (CD14⁺CD16⁺), NKT and CD56^dimNK cells isolated from human liver, but not on parenchymal or other non‐parenchymal hepatic cell types. Membrane‐bound uPAR was rapidly cleaved from monocytes upon inflammatory stimulation by lipopolysaccharide (LPS) and partially by co‐cultured lymphocytes.Conclusions: Similar to its prognostic properties in patients with sepsis or cirrhosis, intrahepatic uPAR activation and serum suPAR concentrations might serve as an interesting biomarker in ALF.

Patienten mit Leberzirrhose haben aufgrund der portalen Hypertension und der hämorrhagischen Diathese ein hohes Risiko für schwere gastrointestinale Blutungen (GIB), die regelhaft auch eine intensivmedizinische Therapie erfordern. Wir analysierten Häufigkeit und individuelle Prognosefaktoren für GIB von Zirrhose-Patienten einer gastroenterologisch geleiteten internistischen Intensivstation retrospektiv für die Jahre 1999 − 2010. Von 7376 behandelten Patienten der Intensivstation wiesen 650 (8,8 %) eine Leberzirrhose auf. Patienten mit Leberzirrhose waren überproportional häufig in der Gruppe der Intensivpatienten vertreten, die wegen einer schweren GIB aufgenommen wurden (23,2 % mit Zirrhose von 711 Patienten mit GIB bei Aufnahme). Zudem zeigten sie ein signifikant erhöhtes Risiko, während des Intensivaufenthalts eine GIB zu entwickeln (40,9 % mit Zirrhose von 44 Patienten mit GIB im Verlauf). Neben der erwarteten Häufung von Varizenblutungen (64,4 %) zeigten Zirrhose-Patienten auch ein signifikant erhöhtes Risiko für nicht variköse GIB (28,5 %). Als unabhängige Risikofaktoren für die Letalität der GIB bei intensivpflichtigen Zirrhose-Patienten konnten der MELD-Score und eine invasive Beatmung identifiziert werden. Patienten mit Leberzirrhose und schwerer GIB zeigten eine verschlechterte Prognose (Letalität 26,1 % mit Zirrhose vs. 6,8 % ohne Zirrhose), insbesondere bei Neuauftreten einer schweren GIB im Behandlungsverlauf. Verbesserte Behandlungskonzepte und neue Therapiestrategien sind erforderlich, um die derzeit kritische Prognose dieser Hochrisikopatienten zu verbessern. Due to portal hypertension and bleeding disorders, patients with liver cirrhosis are at increased risk for severe gastrointestinal bleedings (GIB), commonly requiring therapy at the intensive care unit (ICU). In order to identify epidemiological and prognostic factors for GIB in cirrhotic patients, we retrospectively analysed patients from our medical ICU from 1999 to 2010. Among 7376 critically ill patients, 650 (8.8 %) were diagnosed with liver cirrhosis. Hepatic cirrhosis was frequently found in ICU patients admitted due to severe GIB (23.2 % of 711 patients had cirrhosis). Moreover, patients with cirrhosis were at increased risk to develop severe GIB during intensive care treatment (40.9 % of 44 patients with GIB during ICU stay had cirrhosis). Besides the high rate of variceal bleedings (64.4 %) in cirrhotic patients, non-variceal haemorrhages were also common (28.5 %). We identified the MELD score and necessity of mechanical ventilation as independent risk factors for mortality in cirrhotic patients with severe GIB. Patients with liver cirrhosis and severe GIB had significantly impaired prognosis (case-related fatality rate of 26.1 % with cirrhosis vs. 6.8 % without cirrhosis), especially in cases of newly developed GIB during ICU therapy. Advanced therapeutic approaches and novel strategies are warranted to improve the critical prognosis of these high-risk patients. ¹ Diese Autoren teilen sich die Erstautorenschaft.

In systemic inflammation and sepsis, endothelial activation and microvascular dysfunction are characteristic features that promote multiorgan failure. As symmetric dimethylarginine (SDMA) impacts vascular tension and integrity via modulating nitric oxide (NO) pathways, we investigated circulating SDMA in critical illness and sepsis. 247 critically ill patients (160 with sepsis, 87 without sepsis) were studied prospectively upon admission to the medical intensive care unit (ICU) and on day 7, in comparison to 84 healthy controls. SDMA serum levels were significantly elevated in critically ill patients at admission to ICU compared to controls and remained stably elevated during the first week of ICU treatment. The highest SDMA levels were found in patients with sepsis. SDMA levels closely correlated with disease severity scores, biomarkers of inflammation, and organ failure (renal, hepatic, and circulatory). We identified SDMA serum concentrations at admission as an independent prognostic biomarker in critically ill patients not only for short-term mortality at the ICU but also for unfavourable long-term survival. Thus, the significant increase of circulating SDMA in critically ill patients indicates a potential pathogenic involvement in endothelial dysfunction during sepsis and may be useful for mortality risk stratification at the ICU.

Introduction: Hepatic dysfunction is a common finding in critically ill patients on the ICU and directly influences survival. Liver stiffness can be measured by the novel method of transient elastography (fibroscan) and is closely associated with hepatic fibrosis in patients with chronic liver disease, but also is increased in patients with acute hepatitis, acute liver failure and cholestasis. We investigated liver stiffness as a potentially useful tool for early detection of patients with hepatic deterioration and risk stratification with respect to short- and long-term mortality.Methods: We prospectively evaluated 108 consecutive critically ill patients at our medical intensive care unit (ICU) with subsequent longitudinal liver stiffness measurements (admission, Day 3, Day 7 and weekly thereafter) during the course of ICU treatment. Outcome was followed after discharge (median observation time 237 days).Results: Liver stiffness could be reliably measured in 71% of ICU patients at admission (65% at Day 3, 63% at Day 7). Critically ill patients (n= 108) had significantly increased liver stiffness compared to sex- and age-matched standard care patients (n= 25). ICU patients with decompensated cirrhosis showed highest liver stiffness, whereas other critical diseases (for example, sepsis) and comorbidities (for example, diabetes, obesity) did not impact stiffness values. At admission to the ICU, liver stiffness is closely related to hepatic damage (liver synthesis, cholestasis, fibrosis markers). During the course of ICU treatment, fluid overload (renal failure, volume therapy) and increased central venous pressure (mechanical ventilation, heart failure) were major factors determining liver stiffness. Liver stiffness values > 18 kilopascal (kPa) at ICU admission were associated with increased ICU and long-term mortality, even in non-cirrhotic patients.Conclusions: Considering that liver stiffness cannot be validly measured in about 30% of ICU patients, transient elastography performed at ICU admission might be a useful tool to early identify liver dysfunction and predict mortality in critically ill patients at a medical ICU.