Enrico Maria Zardi

Neuropsychiatric systemic lupus erythematosus: Tools for the diagnosis

Neurological involvement is considered to be a serious complication of systemic lupus erythematosus (SLE). Neuroimaging plays an important role in detecting neurological abnormalities in SLE patients. Conventional magnetic resonance imaging (cMRI) is generally the most valid neuroimaging technique for detecting alterations in the central and peripheral nervous systems. However it may occasionally fail in neuropsychiatric SLE (NPSLE). This is especially the case when the image is not very clear and may depend on the wide variety of neurological and psychiatric manifestations that define this disease. During the last twenty years, this has led to the testing of other radiological instruments, such as single photon emission computed tomography (SPECT), which is complementary to cMRI and seems to furnish additional information, and colour Doppler sonography, which provides minimal additional benefits. Our paper aims to provide a general overview of NPSLE, focusing particularly on the strengths and weaknesses of modern neuroimaging.

Endothelial dysfunction and vascular stiffness in systemic lupus erythematosus: Are they early markers of subclinical atherosclerosis?

In systemic lupus erythematosus (SLE), the risk of development of cardiovascular disease is dramatically increased. Inflammatory and immune-mediated mechanisms, favouring early alterations of the arterial wall are strongly involved in promoting the development of atherosclerosis (ATS) in young SLE patients. In SLE, sonographic measurements of carotid intima-media thickness are able to recognize clinical, but not always subclinical, ATS. On the contrary, assessment of endothelial function and vascular stiffness through sonography-based techniques may be useful to reveal or exclude subclinical ATS. More efforts should be done to find a comprehensive approach to the study of subclinical ATS in SLE patients, since an early diagnosis may have a significant value in preventing the development of major vascular diseases.

Portosystemic shunts in a large cohort of patients with liver cirrhosis: detection rate and clinical relevance

BackgroundThis study aimed to determine the detection rate and clinical relevance of portosystemic collaterals.MethodsWe studied 326 cirrhotics. Portosystemic collaterals, portal vein diameter, and splenic area were evaluated by color Doppler sonography; esophageal varices were detected by endoscopy.ResultsOf the cirrhotics, 130 had portosystemic collaterals (39.9% total, left gastric vein 11%, paraumbilical vein 7.4%, splenorenal shunts 13.8%, and combined shunts 7.7%). Cirrhotics without portosystemic collaterals or with a paraumbilical vein had a significantly narrower portal vein diameter than cirrhotics with a left gastric vein (P < 0.001). Cirrhotics with a paraumbilical vein had a significantly smaller splenic area than cirrhotics with a left gastric vein (P < 0.001), splenorenal shunts (P < 0.001), combined shunts (P < 0.001), or without portosystemic collaterals (P < 0.05). A significant association between portosystemic collaterals and Child’s classes or presence and type of esophageal varices was found (P < 0.0001 and P = 0.0004, respectively). The highest prevalence of Child’s class C and large (F-3) esophageal varices was found in cirrhotics with a left gastric vein (41.7% and 36.1%, respectively), whereas esophageal varices were absent in 47.4% of cirrhotics without portosystemic collaterals and in 58.3% of cirrhotics with a paraumbilical vein.ConclusionsThe left gastric vein is associated with some sonographic and clinical markers of disease severity, whereas the absence of portosystemic collaterals or the presence of paraumbilical veins seems to identify cirrhotics with markers predictive of a more favorable clinical course.

TNF-α and growth hormone resistance in patients with chronic liver disease

Liver cirrhosis is characterized by a severe impairment of the growth hormone/insulin-like growth factor-1 (GH-IGF-1) axis, that is, acquired GH resistance. The condition of the GH-IGF-1 axis in the phase of chronic liver disease (CLD) preceding cirrhosis, however, remains uncertain. The origin of GH resistance during CLD is multifactorial, and to date, the liver functional mass is considered to play a major role. Although proinflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1β, were found to be elevated in patients with CLD and were shown to induce a state of GH resistance in other disease models, their involvement in the pathogenesis of GH resistance during CLD has never been investigated. We characterized the GH-IGF-1 axis by analyzing the individual components of the axis (GH, IGF-1, IGF-binding protein-3 [IGFBP-3], acid-labile subunit [ALS]) and the corresponding ratios (GH/IGF-1, GH/IGFBP-3, and GH/ALS) and verified the links with circulating proinflammatory cytok...

Invasive and non-invasive techniques for detecting portal hypertension and predicting variceal bleeding in cirrhosis: A review

Abstract Portal hypertension is a severe syndrome that may derive from pre-sinusoidal, sinusoidal, and post-sinusoidal causes. As a consequence, several complications (i.e. ascites, oesophageal varices) may develop. In sinusoidal portal hypertension, hepatic venous pressure gradient (HVPG) is a reliable method for defining the grade of portal pressure, establishing the effectiveness of the treatment, and predicting the occurrence of complications; however, some questions exist regarding its ability to discriminate bleeding from non-bleeding varices in cirrhotic patients. Other imaging techniques (transient elastography, endoscopy, endosonography, and duplex Doppler sonography) for assessing causes and complications of portal hypertensive syndrome are available and may be valuable for the management of these patients. In this review, we evaluate invasive and non-invasive techniques currently employed to obtain a clinical prediction of deadly complications, such as variceal bleeding in patients affected by sinusoidal portal hypertension, in order to create a diagnostic algorithm to manage them. Again, HVPG appears to be the reference standard to evaluate portal hypertension and monitor the response to treatment, but its ability to predict several complications and support management decisions might be further improved through the diagnostic combination with other imaging techniques.

Which clinical and sonographic parameters may be useful to discriminate NASH from steatosis

Background The natural history of nonalcoholic steatohepatitis (NASH) includes the passage through steatosis. Goal To retrospectively evaluate the usefulness of sonographic parameters compared to histological diagnosis when differentiating steatosis from NASH. Study This retrospective study reviewed records of patients with steatosis from databases of our Departments, selecting only those who had been diagnosed by sonography and liver biopsy [64 males (63.82%); 30 females (36.18%)]. Results Attenuation of the echo amplitude (P<0.05; odds ratio (OR): 3.43; confidence interval (CI): 1.02-11.57), focal fat sparing (P<0.05; OR: 3; CI: 1.02-11.88) and splenic diameter (P<0.05; OR: 1.66; CI: 1.04-3.26) were independent predictors of NASH. A significantly higher association of attenuation of the echo amplitude, enlarged splenic diameter, and presence of focal fat sparing was observed in NASH patients (P<0.01). Conclusions It is very difficult to build a predictive system to distinguish NASH from steatosis based on sonographic scores. However, it is already possible to differentiate NASH from steatosis by combining 3 simple sonographic parameters: attenuation of the echo amplitude, enlarged splenic diameter, and presence of focal fat sparing.

Isolated hepatocytes versus hepatocyte spheroids: in vitro culture of rat hepatocytes.

The use of hepatocytes that express liver-specific functions to develop an artificial liver is promising. Unfortunately, the loss of specialized liver functions (dedifferentiation) is still a major problem. Different techniques, such as collagen entrapment, spherical multicellular aggregates (spheroids), and coculture of hepatocytes with extracellular matrix, have been used to improve the performance of hepatocytes in culture. The aim of this study was to compare two different models of hepatocyte isolation in culture: isolated hepatocytes (G1) and hepatocyte spheroids (60% hepatocytes, 40% nonparenchymal cells, and extracellular matrix) (G2). To test functional activity of hepatocytes, both synthetic and metabolic, production of albumin and benzodiazepine transformation into metabolites was tested. G2 showed a high albumin secretion, while a decrease after 15 days of culture in G1 was noted. Diazepam metabolites were higher in G2 than in G1 in all samples, but had statistical significance at days 14 and 21 (p < 0.01). The glycogen content, after 30 days of culture, was very low in G1 (14.2 ± 4.4%), while in G2 it was 72.1 ± 2.6% (p < 0.01). Our study confirms the effectiveness of a culture technique with extracellular matrix and nonparenchymal cells. Maintenance of a prolonged functional activity has been related to restoration of cell polarity and close cell-to-cell contact. We showed that isolated hepatocytes maintain their functional activity for a period significantly reduced, when compared to the hepatocyte spheroids. We confirmed the role of extracellular matrix as a crucial component to promote hepatocyte homeostasis, and the close link between cellular architecture and tissue-specific functions.

How to predict subclinical atherosclerosis in systemic lupus erythematosus

Autoimmunity and atherosclerosis (ATS) are linked: ANA positivity is associated with decreased carotid elasticity in women [1]. Subclinical ATS is an asymptomatic but highly prevalent condition of vascular disease [2] and, in patients with SLE, may develop at an early age due to inflammatory and immune-mediated mechanisms, oxidative stress and endothelial dysfunction [3]. An early diagnosis of subclinical ATS in young patients with SLE is preferable for a more effective immunosuppressive treatment that may reduce the development of major cardiovascular complications and improve the outcome of the disease. Assessment of endothelial dysfunction, vascular stiffness and intima-media thickness (IMT) are powerful tools in the evaluation of subclinical ATS [4]. Endothelial dysfunction has shown predictive value in the long-term progression and cardiovascular event rates of ATS [5]. The pathophysiology of ATS includes endothelial dysfunction and inflammation that act on the vascular wall affecting its permeability, increasing its stiffness and, eventually, its thickness. Before ATS develops, all these mechanisms are activated and favour an increased autoantibody production and deposition of immune complexes in the vascular wall; oxLDL forms complexes with b2-glycoprotein I (b2GPI) or CRP, or both [6]. Circulating oxLDL/b2GPI immune complexes captured by macrophage Fcg receptors promote foam cell formation leading to the development of fatty streaks in the arterial wall that may eventually evolve into atherosclerotic plaques [6]. Chronic activation of the immune system supports the pro-inflammatory state and the damaged endothelium is unable to maintain physiological vascular wall conditions, thus opening the window of opportunity that leads to the development of clinical ATS. Therefore, endothelial dysfunction and vascular stiffness precede the increase in IMT, as has been observed in interesting studies on carotids of children and adults with ATS and familial hypercholesterolaemia [4, 7]. To predict subclinical ATS in SLE better, evaluating lupusrelated factors is necessary; indeed, they are better associated with carotid ATS than traditional risk factors alone. Endothelial dysfunction and vascular stiffness, associated with lupus-related factors such as chronic inflammation, immune system activation, metabolic and genetic alterations, large use of CSs and SLE disease activity and duration, may predict subclinical ATS, an asymptomatic but potentially dangerous condition. Several invasive and non-invasive imaging techniques may be useful in assessing endothelial dysfunction and arterial stiffness. Unfortunately, while wide variation in reproducibility is reported in endothelial function measurements, due to both differences in technical protocols and the impact of physiological factors on flow-mediated dilation, this variation is considerably less when measuring IMT. We prefer to use non-invasive techniques, such as sonography-based techniques (equipped with an internal ECG monitor), because they are less expensive, easy to use and easily tolerated by patients. We showed the presence of increased stiffness parameters in SLE patients with normal IMT (<0.6 mm) by means of an M-Mode ultrasonography with synchronous ECG measuring the major increase and reduction in the vessel diameter of the common carotid artery during heart cycles, applying the equations shown in Fig. 1. Clinical ATS (change in plaque echogenicity and plaque progression) is efficiently revealed and monitored by sonography and pulse-wave Doppler sonography, respectively. However, to prevent clinical ATS, strategies should rely on identification of subclinical ATS through the screening of early established markers of cardiovascular risk such as endothelial dysfunction, vascular stiffness and IMT. Monitoring of carotid IMT excellently evaluates risk stratification in hypertensive patients, pharmacological efficacy in clinical trials and rate of progression of ATS before the formation of plaque. A meta-analysis showed that IMT significantly increased in populations with SLE disease compared with ageand sex-matched healthy controls [8]. IMT is a surrogate marker for atherosclerotic disease when deciding therapeutic strategies in lupusmediated atherogenesis [9]. However, a debatable point is that SLE and control subjects may show similar values of carotid IMT, which is reported in several studies [10]. Moreover, a significantly lower mean IMT but a higher prevalence of plaque in SLE compared with control subjects was observed. On the basis of physiopathology and according to some authors [4, 7], endothelial dysfunction and vascular stiffness precede the increase of IMT in subclinical ATS; they may be viewed as important predictors of subclinical ATS

Hemodynamic effects of a prostacyclin analog (iloprost) on portal flow velocity and volume and visceral artery circulation in patients with lower limb arteriopathy.

Previous studies demonstrated that iloprost improves the peripheral circulation. In this study, we examined, by Doppler sonography, portal flow velocity (cm/s) and volume (mL/min), and resistance index (RI) of visceral arteries in 23 patients before and after 7 days of iloprost infusion. Statistically significant hemodynamic changes were only seen in portal vein (pre-iloprost vs. post-iloprost treatment mean portal flow velocity and volume values: 23.9 cm/s vs. 29.0 cm/s, p < 0.001 and 1824.6 mL/min vs. 2294.4 mL/min, p < 0.001, respectively). On the other hand, the interlobar renal artery RI, reduced after iloprost treatment in most patients, was not statistically significant; conflicting results were obtained on the hepatic and mesenteric arteries. Our results indicate that iloprost significantly increases portal flow velocity and volume. The understanding of the mechanism through which iloprost plays a role in portal microcirculation could be useful for its new medical indications in liver hemodynamic disorders.

Prostacyclin in liver disease: a potential therapeutic option.

Complex molecular and cellular mechanisms are involved in the initiation and progression of hepatic fibrosis. Recent studies have shown that hepatic stellate cells, endothelin, cytokines and prostacyclin play crucial roles in this pathology. Prostacyclin exerts vasorelaxant, antioxidant and antifibrotic properties that prevent the development of fibrosis and cirrhosis in liver diseases. In this editorial, the authors discuss some of the molecular and cellular mechanisms involved in the initiation and progression of liver fibrosis and the role played by prostacyclin in counteracting it. At the moment, however, only limited information is available from clinical studies demonstrating the effectiveness of prostacyclin in liver diseases and this makes it difficult to draw any conclusions; further efforts are necessary to verify whether prostacyclin, alone or in combination with other drugs, may be a valid therapeutic option in liver diseases.