No abstract

Albumin is a negatively charged, relatively small protein synthesized by liver cells. Is the most abundant protein in extracellular fluid and accounts for about 70% of the plasma colloid osmotic pressure. Therefore it plays a crucial role in regulating fluid distribution in the body. In addition, albumin possesses functional domains with important non-oncotic properties, such as potent anti-oxydant and scavenging activities, binding of highly toxic reactive metal species and a great amount of endogenous and exogenous substances. We have recently learned that albumin in cirrhosis undergoes a number of post-transcriptional changes that greatly impair its non-oncotic properties. The overall assessment of these changes clearly shows that the relative abundance of the native form of albumin is significantly reduced in hospitalized patients with cirrhosis and that these abnormalities worsen in parallel with the increasing severity of the disease. Thus, it is time to abandon the concept of serum albumin concentration and refer to the effective albumin concentration, that is the native intact albumin. Given the pathophysiological context in which we use human albumin in patients with cirrhosis, who are characterized by peripheral vasodilation and a low-grade but sustained inflammatory state, the use of albumin in patients with cirrhosis should aim at enhancing effective hypovolemia and exploiting its antioxidant and scavenging activities. The indications for the use of albumin in cirrhosis that clearly emerge from evidence-based medicine are represented by conditions characterized by an acute aggravation of effective hypovolemia and inflammation, such as such post-paracentesis circulatory dysfunction, spontaneous bacterial peritonitis, and hepatorenal syndrome. Other indications to the use of albumin that still require further studies are represented by bacterial infections other than spontaneous bacterial peritonitis, hepatic encephalopathy and long-term treatment of ascites, which has been debated for the last half-century.

Endogenous cannabinoids (EC) are ubiquitous lipid signalling molecules providing different central and peripheral effects that are mediated mostly by the specific receptors CB1 and CB2. The EC system is highly upregulated during chronic liver disease and consistent experimental and clinical findings indicate that it plays a role in the pathogenesis of liver fibrosis and fatty liver disease associated with obesity, alcohol abuse and hepatitis C. Furthermore, a considerable number of studies have shown that EC and their receptors contribute to the pathogenesis of the cardio-circulatory disturbances occurring in advanced cirrhosis, such as portal hypertension, hyperdynamic circulatory syndrome and cirrhotic cardiomyopathy. More recently, the EC system has been implicated in the development of ascites, hepatic encephalopathy and the inflammatory response related to bacterial infection. Rimonabant, a selective CB1 antagonist, was the first drug acting on the EC system approved for the treatment of obesity. Unfortunately, it has been withdrawn from the market because of its neuropsychiatric side effects. Compounds able to target selectively the peripheral CB1 receptors are under evaluation. In addition, molecules stimulating CB2 receptor or modulating the activity of enzymes implicated in EC metabolism are promising areas of pharmacological research. Liver cirrhosis and the related complications represent an important target for the clinical application of these compounds.

Background Clinical and biochemical data suggest that autoimmune diseases are associated with endothelial dysfunction and increased atherosclerosis. We have previously shown that asymmetric dimethylarginine (ADMA) levels and coronary flow reserve (CFR) are impaired in patients with early rheumatoid arthritis (1), but it is not known whether the same is true for patients with primary Sjögren’s syndrome (pSS). Objectives To investigate sub-clinical cardiovascular involvement in pSS patients by means of ADMA, coronary flow reserve (CFR), intima media thickness (cIMT), pulse wave velocity (PWV) and myocardial deformation. Methods The study involved 22 outpatients with pSS (6 males, 16 females; mean age 60.14±7.81 years) and no documentable cardiovascular disease, and 22 age- and gender-matched controls. Dipyridamole transthoracic stress echocardiography was used to evaluate wall motion and CFR in the distal segment of the left anterior descending coronary artery before and after dipyridamole infusion (0.84 mg/kg over six minutes). A CFR value of <2.5 was considered a sign of impaired coronary function. We also evaluated cIMT arterial stiffness PWV and plasma ADMA levels, and made a speckle tracking echocardiography (STE) analysis. Results All of the patients were affected by pSS and most were being treated with hydroxychloroquine (HCQ) at a dose of 400 mg/day. They were also ANA or RF and anti-SSB or anti-SSA positive. There were no significant differences in ejection fraction (EF) or E/A ratios between the patients and controls. Although within the normal range, the patients’ CFR was lower than that of the controls (median 2.70; IQR 2.40-2.90 vs 3.20; IQR 3.06-3.33; p <0.0001), whereas their ADMA levels were significantly higher (median 0.81 mM; IQR 0.79-0.85 mM vs 0.54 mM; IQR 0.52-0.58 mM; p< 0.0001). Both left and right PWV values were significantly higher in the patients than in the controls (median 8.8 m/s right and 8.9 m/s left vs 6.86 and 6.89 m/s, p<0.0001), whereas cIMT was substantially similar in the two groups (0.60 mm, IQR 060-0.70 mm vs 0.60 mm, IQR 0.50-0.70, p=NS). Speckle tracking analysis was significantly different between the two groups, with longitudinal strain deformation in the apical four chambers view (Long. ɛ 4c) (median 15.28%, IQR 12.30-16.20% vs 19.80%, IQR 19.30-20.40%, p<0.0001) and radial strain deformation in short axis view (Radial ɛ SAX) (median 26.00%, IQR 24.26-31.90% vs 31.50%, IQR 28.30-34.50%, p=0.02) being significantly less in the pSS patients. Conclusions Higher ADMA levels suggest the presence of endothelial dysfunction and sub-clinical atherosclerosis in pSS patients, even in the case of a normal CFR. This finding is supported by the PWV values, which were higher in the pSS patients. These preliminary data indicate that ADMA levels and PWV values may be useful markers for identifying early endothelial dysfunction in pSS patients. References Turiel M, Atzeni F, Tomasoni L, et al Non-invasive assessment of coronary flow reserve and ADMA levels: a case-control s...