Proton pump inhibitor treatment aggravates bacterial translocation in patients with advanced cirrhosis and portal hypertension.

IMPORTANCE: Long-term prescription of proton pump inhibitors (PPIs) in patients with cirrhosis is common practice. However, in recent years, several observational studies have reported increased complications and negative prognostic effects of PPI treatment in these patients. Judging the significance of these associations is complicated by the fact that a plausible underlying pathomechanism has not been identified so far. In the present study, we address this important issue by investigating the impact of PPI treatment on subclinical bacterial translocation from the gut into the blood stream in patients with advanced cirrhosis and portal hypertension. Indeed, we report significantly aggravated bacterial translocation in cirrhosis patients receiving PPI treatment. This finding is highly relevant, as bacterial translocation is known to promote the development of complications and impair prognosis in patients with cirrhosis. Hence, the present study could establish a plausible link between PPI treatment and adverse effects in cirrhosis.

Prognostic Value of the CLIF-C AD Score in Patients With Implantation of Transjugular Intrahepatic Portosystemic Shunt.

Prognostic assessment of patients with liver cirrhosis allocated for implantation of a transjugular intrahepatic portosystemic shunt (TIPS) is a challenging task in clinical practice. The aim of our study was to assess the prognostic value of the CLIF-C AD (Acute Decompensation) score in patients with TIPS implantation. Transplant-free survival (TFS) and 3-month mortality were reviewed in 880 patients who received de novo TIPS implantation for the treatment of cirrhotic portal hypertension. The prognostic value of the CLIF-C AD score was compared with the Model for End-Stage Liver Disease (MELD) score, Child-Pugh score, and albumin-bilirubin (ALBI) score using Harrell's C concordance index. The median TFS after TIPS implantation was 40.0 (34.6-45.4) months. The CLIF-C AD score (c = 0.635 [0.609-0.661]) was superior in the prediction of TFS in comparison to MELD score (c = 0.597 [0.570-0.623], P = 0.006), Child-Pugh score (c = 0.579 [0.552-0.606], P < 0.001), and ALBI score (c = 0.573 [0.545-0.600], P < 0.001). However, the CLIF-C AD score did not perform significantly better than the MELD-Na score (c = 0.626 [0.599-0.653], P = 0.442). There were no profound differences in the scores' ranking with respect to indication for TIPS implantation, stent type, or underlying liver disease. Subgroup analyses revealed that a CLIF-C AD score >45 was a predictor of 3-month mortality in the supposed low-risk group of patients with a MELD score ≤12 (14.7% vs. 5.1%, P < 0.001). Conclusion: The CLIF-C AD score is suitable for prognostic assessment of patients with cirrhotic portal hypertension receiving TIPS implantation. In the prediction of TFS, the CLIF-C AD score is superior to MELD score, Child-Pugh score, and ALBI score but not the MELD-Na score.

Blood reelin in the progression of chronic liver disease.

PURPOSE: Reelin is an extracellular matrix protein originally found to be associated with neuropsychiatric disorders. Recent findings indicate, that reelin may also play an important role in the process of liver fibrosis as well as in the development of hepatocellular carcinoma (HCC). Against this background, the aim of our study was to explore alterations in blood reelin levels in different stages of chronic liver diseases. PATIENTS AND METHODS: We analyzed blood samples of patients with chronic liver disease without liver fibrosis (n â€‹= â€‹25), with liver fibrosis (n â€‹= â€‹36), with liver cirrhosis (n â€‹= â€‹74), with HCC (n â€‹= â€‹26) as well as of healthy controls (n â€‹= â€‹15). Blood reelin concentrations were determined utilizing an enzyme-linked immunosorbent assay. RESULTS: Blood reelin levels were significantly elevated in patients who had liver fibrosis or cirrhosis compared to patients without liver fibrosis and healthy controls (13.9 (10.2-21.1) ng/ml vs. 11.2 (8.8-16.8) ng/ml, p â€‹= â€‹0.032). Importantly, patients with HCC displayed significantly higher reelin concentrations compared to patients with liver cirrhosis alone (27.0 (17.3-35.9) ng/ml vs. 16.6 (11.0-22.7) ng/ml, p â€‹< â€‹0.001). Blood reelin was not relevantly linked to liver function, inflammation and etiology of liver disease. CONCLUSIONS: Our results demonstrate, that blood reelin levels are altered in different stages of chronic liver disease, which makes reelin a potential biomarker in this setting. This may be especially relevant with regard to its use as an additional tumor marker of HCC.

Plasma Cyclic Guanosine Monophosphate Is a Promising Biomarker of Clinically Significant Portal Hypertension in Patients With Liver Cirrhosis.

Introduction: Despite intensive research, reliable blood-derived parameters to detect clinically significant portal hypertension (CSPH) in patients with cirrhosis are lacking. As altered homeostasis of cyclic guanosine monophosphate (cGMP), the central mediator of vasodilatation, is an essential factor in the pathogenesis of portal hypertension, the aim of our study was to evaluate plasma cGMP as potential biomarker of cirrhotic portal hypertension. Methods: Plasma cGMP was analyzed in cirrhotic patients with CSPH (ascites, n = 39; esophageal varices, n = 31), cirrhotic patients without CSPH (n = 21), patients with chronic liver disease without cirrhosis (n = 11) and healthy controls (n = 8). cGMP was evaluated as predictor of CSPH using logistic regression models. Further, the effect of transjugular intrahepatic portosystemic shunt (TIPS) placement on plasma cGMP was investigated in a subgroup of cirrhotic patients (n = 13). Results: Plasma cGMP was significantly elevated in cirrhotic patients with CSPH compared to cirrhotic patients without CSPH [78.1 (67.6-89.2) pmol/ml vs. 39.1 (35.0-45.3) pmol/l, p < 0.001]. Of note, this effect was consistent in the subgroup of patients with esophageal varices detected at screening endoscopy who had no prior manifestations of portal hypertension (p < 0.001). Cirrhotic patients without CSPH displayed no significant elevation of plasma cGMP compared to patients without cirrhosis (p = 0.347) and healthy controls (p = 0.200). Regression analyses confirmed that cGMP was an independent predictor of CSPH (OR 1.042, 95% CI 1.008-1.078, p = 0.016). Interestingly, portal decompression by TIPS implantation did not lead to normalization of plasma cGMP levels (p = 0.101). Conclusions: Plasma cGMP is a promising biomarker of CSPH in patients with cirrhosis, especially with respect to screening for esophageal varices. The lacking normalization of plasma cGMP after portal decompression suggests that elevated plasma cGMP in cirrhotic portal hypertension is mainly a correlate of systemic and splanchnic vasodilatation, as these alterations have been shown to persist after TIPS implantation.

Inhibition of macrophage proliferation dominates plaque regression in response to cholesterol lowering.

Statins induce plaque regression characterized by reduced macrophage content in humans, but the underlying mechanisms remain speculative. Studying the translational APOE*3-Leiden.CETP mouse model with a humanized lipoprotein metabolism, we find that systemic cholesterol lowering by oral atorvastatin or dietary restriction inhibits monocyte infiltration, and reverses macrophage accumulation in atherosclerotic plaques. Contrary to current believes, none of (1) reduced monocyte influx (studied by cell fate mapping in thorax-shielded irradiation bone marrow chimeras), (2) enhanced macrophage egress (studied by fluorescent bead labeling and transfer), or (3) atorvastatin accumulation in murine or human plaque (assessed by mass spectrometry) could adequately account for the observed loss in macrophage content in plaques that undergo phenotypic regression. Instead, suppression of local proliferation of macrophages dominates phenotypic plaque regression in response to cholesterol lowering: the lower the levels of serum LDL-cholesterol and lipid contents in murine aortic and human carotid artery plaques, the lower the rates of in situ macrophage proliferation. Our study identifies macrophage proliferation as the predominant turnover determinant and an attractive target for inducing plaque regression.

Acute pancreatitis and vasoplegic shock associated with leptospirosis - a case report and review of the literature.

BACKGROUND: Leptospirosis or Weil's disease is caused by pathogenic spirochete bacteria called Leptospira. It is considered the most common zoonosis in the world and is usually transmitted by urine of rodents and dogs with an incubation time of 7-14 days. The clinical spectrum ranges from a subclinical infection to a fulminant septic course. CASE PRESENTATION: Here, we report the case of a German patient with acute pancreatitis associated with Leptospira interrogans causing fulminant septic shock. The patient was successfully treated with intravenous antibiotics and left the hospital fully recovered after 18 days. CONCLUSIONS: To our knowledge, this is the first case of leptospirosis with acute pancreatitis as the leading clinical manifestation in Central Europe. Serologic and molecular genetic tests for leptospirosis should be considered, if no other causes for pancreatitis can be identified.