Neutrophil gelatinase-associated lipocalin is a biomarker of acute-on-chronic liver failure and prognosis in cirrhosis.

BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is a syndrome that occurs in cirrhosis characterized by organ failure(s) and high mortality rate. There are no biomarkers of ACLF. The LCN2 gene and its product, neutrophil gelatinase-associated lipocalin (NGAL), are upregulated in experimental models of liver injury and cultured hepatocytes as a result of injury by toxins or proinflammatory cytokines, particularly Interleukin-6. The aim of this study was to investigate whether NGAL could be a biomarker of ACLF and whether LCN2 gene may be upregulated in the liver in ACLF. METHODS: We analyzed urine and plasma NGAL levels in 716 patients hospitalized for complications of cirrhosis, 148 with ACLF. LCN2 expression was assessed in liver biopsies from 29 additional patients with decompensated cirrhosis with and without ACLF. RESULTS: Urine NGAL was markedly increased in ACLF vs. no ACLF patients (108(35-400) vs. 29(12-73)µg/g creatinine; p<0.001) and was an independent predictive factor of ACLF; the independent association persisted after adjustment for kidney function or exclusion of variables present in ACLF definition. Urine NGAL was also an independent predictive factor of 28day transplant-free mortality together with MELD score and leukocyte count (AUROC 0.88(0.83-0.92)). Urine NGAL improved significantly the accuracy of MELD in predicting prognosis. The LCN2 gene was markedly upregulated in the liver of patients with ACLF. Gene expression correlated directly with serum bilirubin and INR (r=0.79; p<0.001 and r=0.67; p<0.001), MELD (r=0.68; p<0.001) and Interleukin-6 (r=0.65; p<0.001). CONCLUSIONS: NGAL is a biomarker of ACLF and prognosis and correlates with liver failure and systemic inflammation. There is remarkable overexpression of LCN2 gene in the liver in ACLF syndrome. LAY SUMMARY: Urine NGAL is a biomarker of acute-on-chronic liver failure (ACLF). NGAL is a protein that may be expressed in several tissues in response to injury. The protein is filtered by the kidneys due to its small size and can be measured in the urine. Ariza, Graupera and colleagues found in a series of 716 patients with cirrhosis that urine NGAL was markedly increased in patients with ACLF and correlated with prognosis. Moreover, gene coding NGAL was markedly overexpressed in the liver tissue in ACLF.

Automated low flow pump system for the treatment of refractory ascites: a single-center experience.

INTRODUCTION: Ascites is a common complication of liver cirrhosis and represents the main cause of hospitalization among patients with cirrhosis. First-line therapy for those patients is the use of diuretics and dietary sodium restriction. However, 10 % of patients per year become therapy refractory to diuretic treatment with the need of repeated high-volume paracentesis or transjugular intrahepatic portosystemic shunt (TIPS). For these patients, an automated pump system (Alfapump/Sequana Medical) was developed. Here, we describe our single-center experience of ten consecutively implanted pump systems. PATIENTS AND METHODS: Between 08/13 and 11/14, ten Alfapump systems were implanted in patients with refractory ascites all suffering from liver cirrhosis. Those patients were treated as a bridge to transplant (4/10) or as an end-stage therapy (6/10). Median follow-up was 165 days (23-379 days). RESULTS: Postimplant, the need of paracentesis could be markedly reduced to a mean of 0.45 (0-4/month) per month. In eight patients, paracentesis was not needed after implantation of the pump system. The median daily output volume was 1000 ml/day (450-2000 ml/day). Prerenal insufficiency was a recurrent complication in the postoperative period. DISCUSSION: The Alfapump system is a useful system in the treatment of patients suffering from therapy refractory ascites. However, due to the high level of comorbidities, careful patient selection and postoperative monitoring are required.

[Therapy of hepatocellular carcinoma before liver transplantation]. / Therapie des hepatozellulären Karzinoms vor Lebertransplantation.

Liver transplantation is the optimal therapy for patients with non-resectable early stage hepatocellular carcinoma (HCC) which is limited to the liver. During the sometimes long waiting period patients usually receive neoadjuvant bridging therapy to avoid tumor progression. The armamentarium of bridging therapies includes local ablative and systemic therapies as well as liver resection. The oncological benefit of neoadjuvant therapy for patients who receive a liver transplantation is unclear; however, bridging therapy keeps patients eligible for transplantation in the formal framework of current allocation rules. Moreover, response to therapy may serve as a surrogate marker for favorable tumor biology and may therefore help to guide the selection process for patients undergoing liver transplantation for HCC.

Acute postinfectious glomerulonephritis associated with Campylobacter jejuni enteritis - a case report and review of the literature on C. jejuni's potential to trigger immunologically mediated renal disease.

Kidney disease is a rare complication of Campylobacter jejuni (C. jejuni) enteritis. We here present the case of an 18-year-old male patient with crampy abdominal pain, vomiting, diarrhea, and fever. Three weeks later urinalysis revealed mild proteinuria and hematuria and a marked raise in serum creatinine was observed. Renal biopsy demonstrated acute endocapillary glomerulonephritis with mesangial IgM (immunoglobuline M) deposits. Extensive workup revealed no signs of skin or joint disease, thus excluding Henoch-Schönlein purpura. Due to persistent abdominal discomfort further gastro-enterological tests were performed and eventually Campylobacter jejuni was isolated from the patient's feces. In the absence of other precipitating factors for renal diseases we presumed an association between the bacterial infection and this postinfectious glomerulonephritis. Over a time period of 6 months the patient's kidney function normalized completely. However, long-term prognosis remains unclear. In addition to the case report, we conducted a review of the literature with results underlining Campylobacter jejuni's potential to trigger various types of immune mediated kidney diseases.

A novel technique for selective NF-kappaB inhibition in Kupffer cells: contrary effects in fulminant hepatitis and ischaemia-reperfusion.

BACKGROUND AND AIMS: The transcription factor nuclear factor kappa B (NF-kappaB) has risen as a promising target for anti-inflammatory therapeutics. In the liver, however, NF-kappaB inhibition mediates both damaging and protective effects. The outcome is deemed to depend on the liver cell type addressed. Recent gene knock-out studies focused on the role of NF-kappaB in hepatocytes, whereas the role of NF-kappaB in Kupffer cells has not yet been investigated in vivo. Here we present a novel approach, which may be suitable for clinical application, to selectively target NF-kappaB in Kupffer cells and analyse the effects in experimental models of liver injury. METHODS: NF-kappaB inhibiting decoy oligodeoxynucleotides were loaded upon gelatin nanoparticles (D-NPs) and their in vivo distribution was determined by confocal microscopy. Liver damage, NF-kappaB activity, cytokine levels and apoptotic protein expression were evaluated after lipopolysaccharide (LPS), d-galactosamine (GalN)/LPS, or concanavalin A (ConA) challenge and partial warm ischaemia and subsequent reperfusion, respectively. RESULTS: D-NPs were selectively taken up by Kupffer cells and inhibited NF-kappaB activation. Inhibition of NF-kappaB in Kupffer cells improved survival and reduced liver injury after GalN/LPS as well as after ConA challenge. While anti-apoptotic protein expression in liver tissue was not reduced, pro-apoptotic players such as cJun N-terminal kinase (JNK) were inhibited. In contrast, selective inhibition of NF-kappaB augmented reperfusion injury. CONCLUSIONS: NF-kappaB inhibiting decoy oligodeoxynucleotide-loaded gelatin nanoparticles is a novel tool to selectively inhibit NF-kappaB activation in Kupffer cells in vivo. Thus, liver injury can be reduced in experimental fulminant hepatitis, but increased at ischaemia-reperfusion.

[64-year old patient with tachycardia and signs of heart failure]. / 64-jähriger Patient mit Herzrasen und Zeichen einer Herzinsuffizienz.

We report on a 64-year old patient with known Morbus Osler and high cardiac output failure due to distinct arterio-venous malformations of the liver. Since the patient suffered from severe right heart insufficiency despite optimized medical therapy, we decided to conduct an interventional occlusion of the hepatic shunts in three single sessions. The transient elevation of transaminases was reversible. After interventional therapy cardiac output decreased from 20 l/min to 15 l/min (25%) leading to a reduction of diuretic dosage and a sustained stabilization of the clinical condition.

JNK inhibition sensitises hepatocellular carcinoma cells but not normal hepatocytes to the TNF-related apoptosis-inducing ligand.

BACKGROUND: cJun terminal kinase (JNK) is constitutively activated in most hepatocellular carcinomas (HCCs), yet its exact role in carcinogenesis remains controversial. While tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is known as a major mediator of acquired immune tumour surveillance, and is currently being tested in clinical trials as a novel cancer therapy, the resistance of many tumours to TRAIL and concerns about its toxicity in vivo represent obstacles to its clinical application. In this study we investigated whether JNK activity in HCC could contribute to the resistance to apoptosis in these tumours. METHODS: The effect of JNK/Jun inhibition on receptor-mediated apoptosis was analysed by pharmacological inhibition or RNA interference in cancer cells and non-tumour cells isolated from human liver or transgenic mice lacking a phosphorylation site for Jun. RESULTS: JNK inhibition caused cell cycle arrest, enhanced caspase recruitment, and greatly sensitised HCC cells but not normal hepatocytes to TRAIL. TRAIL-induced activation of JNK could be effectively interrupted by administration of the JNK inhibitor SP600125. CONCLUSIONS: Expression and TRAIL-dependent feedback activation of JNK likely represent a mechanism by which cancer cells escape TRAIL-mediated tumour surveillance. JNK inhibition might represent a novel strategy for specifically sensitising HCC cells to TRAIL thus opening promising therapeutic perspectives for safe and effective use of TRAIL in cancer treatment.

Q-T interval (QT(C)) in patients with cirrhosis: relation to vasoactive peptides and heart rate.

OBJECTIVE: Prolonged Q-T interval (QT) has been reported in patients with cirrhosis who also exhibit profound abnormalities in vasoactive peptides and often present with elevated heart rate (HR). The aim of this study was to relate QT to the circulating level of endothelins (ET-1 and ET-3) and calcitonin gene-related peptide (CGRP) in patients with cirrhosis. In addition, we studied problems with HR correction of QT. MATERIAL AND METHODS: Forty-eight patients with cirrhosis and portal hypertension were studied during a haemodynamic investigation. Circulating levels of ETs and CGRP were determined by radioimmunoassays. Correction of QT for HR above 60 beats per min was performed using the methods described by Bazett (QT(C)) and Fridericia (QT(F)). RESULTS: Prolonged QT(C) (above 440 ms), found in 56% of the patients, was related to the presence of significant portal hypertension and liver dysfunction (p < 0.05 to 0.001), but not to elevated ET-1, ET-3 or CGRP. When corrected according to Bazett, QT(C) showed no significant relation to differences in HR between patients (r = 0.07, ns). QTF showed some undercorrection of HR (r = -0.36; p < 0.02). During HR variation in the individual patient, QT(C) revealed a small but significant overcorrection (2.6 ms per heartbeat per min; p < 0.001). This value was significantly (p < 0.02) smaller with QTF (1.2 ms per heartbeat per min). CONCLUSIONS: The prolonged QT(C) in cirrhosis is related to liver dysfunction and the presence of portal hypertension, but not to the elevated powerful vasoconstrictor (ET-1) or vasodilator (CGRP, ET-3) peptides. The problems with correction of the QT for elevated HR in cirrhosis are complex, and the lowest HR should be applied for determination of the QT.

[Renal impairment in liver diseases]. / Extrahepatische Manifesta- tionen bei Lebererkrankungen: Niere.

Renal failure in patients with liver disease is mostly none-organic: prerenal failure or hepatorenal syndrome (HRS). In addition there is organic renal failure, mostly acute tubular necrosis (ATN). In order to avoid functional renal failure cautious diuretic treatment as well as intravenous albumin substitution following paracentesis are pivotal. For prophylaxis of HRS patients with spontaneous bacterial peritonitis shall be given albumin infusions in addition to antibiotic treatment. Patients with HRS type I exhibit a very poor prognosis. Liver transplantation is the only established therapy with long-term success. To bridge the time to transplantation TIPS or terlipressin and albumin can be used.

Endothelin and endothelin receptor antagonism in portopulmonary hypertension.

Portopulmonary hypertension (PPHT) is a rare but devastating complication in patients with portal hypertension, characterized by pulmonary arterial obliterative disease with a concomitant rise in pulmonary vascular resistance. A broad body of evidence has accumulated, indicating that endothelin (ET) peptides and their cognate receptors are causally involved in the pathophysiology of pulmonary arterial hypertension (PAH) owing to different aetiologies, including PPHT. In addition, the ET system may be involved in hepatic fibrotic remodelling and portal hypertension. Several experimental models have provided evidence that ET receptor antagonism may have therapeutic potential in PPHT. Initial experience has accumulated during the last 2 years, suggesting that targeting the ET system may have beneficial effects in the clinical setting. In these studies, the orally active, dual ET receptor antagonist bosentan improved pulmonary haemodynamics and functional capacity. These effects were sustained and occurred in the absence of adverse events. If these observations can be corroborated by controlled clinical trials, bosentan would offer several advantages over available therapies, which have major drawbacks owing to their invasive and demanding mode of application.

Hepatitis induced by Noni juice from Morinda citrifolia: a rare cause of hepatotoxicity or the tip of the iceberg?

A 24-year-old female patient presented to her community hospital with mild elevations of serum transaminase and bilirubin levels. Because of multiple sclerosis, she was treated with interferon beta-1a for 6 weeks. After exclusion of viral hepatitis due to hepatitis A-E, interferon beta-1a was withdrawn under the suspicion of drug-induced hepatitis. One week later, she was admitted again to her community hospital with severe icterus. The transaminase and bilirubin levels were highly elevated, and a beginning impairment of the liver synthesis was expressed by a reduced prothrombin time. The confinement to our department occurred with a fulminant hepatitis and the suspicion of beginning acute liver failure. There was no evidence for hepatitis due to potentially hepatotoxic viruses, alcoholic hepatitis, Budd-Chiari syndrome, hemochromatosis, and Wilson's disease. In her serum there were high titers of liver-kidney microsomal type 1 autoantibody; the serum gamma globulin levels were in the normal range. Fine-needle aspiration biopsy of the liver ruled out an autoimmune hepatitis but showed signs of drug-induced toxicity. During the interview, she admitted that for 'general immune system stimulation' she had been drinking Noni juice, a Polynesian herbal remedy made from a tropical fruit (Morinda citrifolia), during the past 4 weeks. After cessation of the Noni juice ingestion, her transaminase levels normalized quickly and were in the normal range within 1 month.

Tumour size is an important predictor for the outcome after liver transplantation for hepatocellular carcinoma.

AIMS: Recently, there is a tendency to expand tumour sizes qualifying for OLT. The present study re-evaluates tumour size and histopathological features as selection criteria for OLT. METHODS: Retrospective analysis of 93 adult HCC patients underwent OLT between June 1985 and December 2003. Median follow-up was 28 months (1-222 months). The Milan criteria were routinely applied since 1994. RESULTS: Five year survival rate of HCC patients was significantly lower than in patients transplanted for benign diseases, 41 and 71%, respectively (p<0.0001). Multivariate analysis revealed that the presence of vascular invasion represents the most significant predictor (p<0.001) affecting the survival rate. Survival was also significantly impaired when the tumour size was >5 cm (p<0.05), whereas the number of nodules had no significant effect on survival. Consequently, the survival rate for HCC fulfilling the Milan criteria histologically improved to 70% since 1994. CONCLUSION: Tumour size has been shown to be the most important pre-operatively detectable predictor for patient survival after OLT.