Project for interventional Oncology LArge-database in liveR Hepatocellular carcinoma - Preliminary CT-based radiomic analysis (POLAR Liver 1.1).

OBJECTIVE: The objective of this study is to find a contrast-enhanced CT-radiomic signature to predict clinical incomplete response in patients affected by hepatocellular carcinoma who underwent locoregional treatments. PATIENTS AND METHODS: 190 patients affected by hepatocellular carcinoma treated using focal therapies (radiofrequency or microwave ablation) from September 2018 to October 2020 were retrospectively enrolled. Treatment response was evaluated on a per-target-nodule basis on the 6-months follow-up contrast-enhanced CT or MR imaging using the mRECIST criteria. Radiomics analysis was performed using an in-house developed open-source R library. Wilcoxon-Mann-Whitney test was applied for univariate analysis; features with a p-value lower than 0.05 were selected. Pearson correlation was applied to discard highly correlated features (cut-off=0.9). The remaining features were included in a logistic regression model and receiver operating characteristic curves; sensitivity, specificity, positive and negative predictive value were also computed. The model was validated performing 2000 bootstrap resampling. RESULTS: 56 treated lesions from 42 patients were selected. Treatment responses were: complete response for 26 lesions (46.4%), 18 partial responses (32.1%), 10 stable diseases (17.9%), 2 progression diseases (3.6%). Area-Under-Curve value was 0.667 (95% CI: 0.527-0.806); accuracy, sensitivity, specificity, positive and negative predictive values were respectively 0.66, 0.85, 0.50, 0.59 and 0.79. CONCLUSIONS: This contrast-enhanced CT-based model can be helpful to early identify poor responder's hepatocellular carcinoma patients and personalize treatments.

Hepatocellular liver injury in hospitalized patients affected by COVID-19: Presence of different risk factors at different time points.

BACKGROUND: Prevalence and clinical impact of increased liver function tests in patients affected by Coronavirus disease 2019 (COVID-19) is controversial. AIMS: This observational study evaluates the prevalence of transaminases elevation in hospitalized patients affected by COVID-19 and investigates the presence of factors associated with hepatocellular injury and with mortality. METHODS: Data of 292 adult patients with confirmed COVID-19 admitted to the Ente Ospedaliero Cantonale (Switzerland) were retrospectively analyzed. RESULTS: Transaminases were increased in about one-third of patients on hospital admission and two-thirds of patients during the hospital stay. On hospital admission, transaminases were more commonly elevated in younger patients, who also reported elevated C reactive protein and a higher degree of respiratory failure. Independent factors associated with abnormal transaminases during hospitalization were drugs, in particular paracetamol (OR=2.67; 95% CI=1.38-5.18; p = 0.004) and remdesivir (OR=5.16; 95% CI=1.10-24.26; p = 0.04). Mortality was independently associated to age (OR = 1.09; 95% CI=1.05-1.13; p<0.001), admission to intensive care unit (OR=5.22; 95% CI=2.28-11.90; p<0.001) and alkaline phosphatase peak (OR=1.01; 95% CI=1.00- 1.01; p = 0.01). CONCLUSIONS: On hospital admission, factors associated with liver damage were linked to demographic and clinical characteristics (age, inflammation and hypoxia) while, during hospitalization, drug treatment was related to development and progression of hepatocellular damage. Mortality was associated with alkaline phosphate peak value.

Prevalence of liver injury and correlation with clinical outcomes in patients with COVID-19: systematic review with meta-analysis.

OBJECTIVE: Liver involvement of SARS-CoV-2 infection has been reported in several papers, but without homogeneous findings. We aimed to systematically review the prevalence of liver involvement in patients with SARS-CoV-2 infection at their hospital admission, and its correlation with disease severity and clinical outcomes in patients with or without pre-existing chronic liver disease. MATERIALS AND METHODS: We systematically searched PubMed, Embase, Web of Science, Medline, PMC, clinical trial registries, and other Coronavirus family publications for studies reporting data on SARS-CoV-2 infection or COVID-19 and liver function tests (LFTs) alterations, as well as clinical course of patients with chronic liver disease or cirrhosis. Case reports, preprints, editorials, reviews were excluded. We also revised literature to describe the background of liver involvement during SARS-CoV-2 infection. RESULTS: 36 studies, including 20724 patients with SARS-CoV-2 infection, were included. The pooled prevalence of LFTs abnormalities at admission was 46.9% (AST 26.5%, ALT 22.8%, GGT 22.5%, ALP 5.7%, tBIL 8.0%). ALT, AST, tBIL were independent predictors of disease severity (ALT OR 1.54, 95% CI 1.17-2.03; AST OR 3.17, 95% CI 2.10-4.77; tBIL OR 2.32, 95% CI 1.18-4.58) and in-hospital mortality (ALT OR 1.48, 95% CI 1.12-1.96; AST OR 4.39, 95% CI 2.68-7.18; tBIL OR 7.75, 95% CI 2.28-26.40). Heterogeneity among studies was high. The few available data also reported that COVID-19 was associated with increased risk of liver decompensation and mortality in patients with liver cirrhosis. CONCLUSIONS: LFTs alterations were reported in up to 47% of unselected patients with COVID-19 and were associated with severe disease or in-hospital mortality. In cirrhotic patients, COVID-19 was associated with high risk of liver decompensation or mortality.

Increased Faecalibacterium abundance is associated with clinical improvement in patients receiving rifaximin treatment.

Compositional and functional alterations of the gut microbiota are involved in the pathogenesis of several gastrointestinal diseases. Rifaximin is often used to induce disease remission due to its eubiotic effects on the gut microbiota. To investigate the correlation between changes in the gut microbiota composition and symptoms improvement in patients who present a clinical response to rifaximin treatment. Patients with ulcerative colitis (UC), Crohn's disease (CD), irritable bowel syndrome (IBS) and diverticular disease (DD) undergoing rifaximin treatment for clinical indication were enrolled in the study. Rifaximin was administered at the dose of 1,200 mg/day for 10 days. Faecal samples were collected at baseline and at the end of treatment; clinical improvement was assessed by Mayo score for UC, CD Activity Index (CDAI) for CD, IBS severity scoring system (IBS-SSS) for IBS and global symptomatic score (GSS) for DD. Twenty-five patients were included in the analysis and a clinical improvement was recorded for 10/25 (40%) of them. Microbial alpha diversity showed a slight increase in clinical responders (P=0.271), while it decreased in patients who did not improved (P=0.05). A significant post-treatment increase in Faecalibacterium abundance was observed in patients with a positive response (log2FC 1.959, P=0.042). Roseburia abundance decreased in both groups, whereas Ruminococcus decreased only in patients who clinically improved. Clinical improvement consequent to rifaximin treatment is associated with an increase in Faecalibacterium abundance. Achieving a positive shift in the gut microbiota composition seems a key event to obtain a clinical benefit from treatment.

Recurrent hepatocellular carcinoma and non-classic adreno-genital syndrome.

OBJECTIVE: Hepatocellular carcinoma (HCC) is one of the most common fatal cancer in the world and androgens are among the possible etiological factors. Congenital adrenal hyperplasia (CAH) is a group of inherited diseases caused by enzyme failure in the steroid biosynthesis of the adrenal cortex, resulting in an augmented 17-hydroxyprogesterone, androstenedione and testosterone production. While the occurrence of testicular adrenal rest tumors and adrenocortical tumors in congenital adrenal hyperplasia is well described in the literature, no data on HCC occurrence are available. CASE PRESENTATION: A 35-years-old Italian man of Caucasian origin, affected by non-classic CAH due to partial 21-hydroxylase deficiency came to observation for revaluation of his adrenal picture. Besides common hormonal and biochemical analysis, an abdomen Magnetic Resonance Imaging was performed, resulting in an 18 mm large nodular lesion between liver segments VII and VIII. Radiological reports matched with an increased serum α-fetoprotein level. A surgical removal of the lesion was performed. After that, several recurrences of the lesion, which was consequently treated by radiofrequency ablation, occurred. Every recurrence was accompanied by an increase in testosterone and steroid hormone binding globulin serum levels. CONCLUSIONS: Our report suggests the need for screening of liver lesions in males affected by this syndrome.

Biliary tract microbiota: a new kid on the block of liver diseases?

The microbiome plays a crucial role in maintaining the homeostasis of the organism. Recent evidence has provided novel insights for understanding the interaction between the microbiota and the host. However, the vast majority of such studies have analyzed the interactions taking place in the intestinal tract. The biliary tree has traditionally been considered sterile under normal conditions. However, the advent of metagenomic techniques has revealed an unexpectedly rich bacterial community in the biliary tract. Associations between specific microbiological patterns and inflammatory biliary diseases and cancer have been recently described. Hence, biliary dysbiosis may be a primary trigger in the pathogenesis of biliary diseases. In particular, recent studies have suggested that microorganisms could play a significant role in the development of gallstones, pathogenesis of autoimmune cholangiopathies and biliary carcinogenesis. Moreover, the intimate connection between the biliary tract, liver and pancreas, could reveal hidden influences on the development of diseases of these organs. Further studies are needed to deepen the comprehension of the influence of the biliary microbiota in human pathology. This knowledge could lead to the formulation of strategies for modulating the biliary microbiota in order to treat and prevent these pathological conditions.

Primary biliary cholangitis development after hepatitis C virus eradication with direct acting antivirals: a case report and review of the literature.

We report the case of an 84-year-old man with asymptomatic chronic hepatitis C virus (HCV) infection treated with direct antiviral agents. At the end of the antiviral therapy laboratory tests showed an abrupt increase in cholestasis parameters and aminotransferases, associated with anti-mitochondria antibodies positivity. Therefore, primary biliary cholangitis (PBC) was diagnosed. The patient was treated with ursodeoxycholic acid achieving a good biochemical response. This is the second case described in literature of PBC onset after HCV eradication with an interferon-free antiviral regimen. In both cases an autoimmune damage of cholangiocytes secondary to the immunological derangement caused by virus clearance may be hypothesized. Indeed, according to the hygiene hypothesis, when two different triggers act simultaneously on the immune system they tend to be mutually inhibitory, and an immune tolerance develops; when one of these triggers disappears (as HCV in this case), the immune system may mount a response against self-antigens, causing autoimmune disorders such as PBC.

Critical analysis of major and ancillary features of LI-RADS v2018 in the differentiation of small (≤ 2 cm) hepatocellular carcinoma from dysplastic nodules with gadobenate dimeglumine-enhanced magnetic resonance imaging.

OBJECTIVE: To evaluate the performance of major features, ancillary features, and categories of Liver Imaging Reporting and Data System (LI-RADS) version 2018 at magnetic resonance (MR) imaging in the differentiation of small hepatocellular carcinoma (HCC) from dysplastic nodules (DNs). PATIENTS AND METHODS: This retrospective study included cirrhotic patients with pathologically proven untreated HCCs and DNs (≤ 2 cm) and liver MR imaging performed with gadobenate dimeglumine contrast agent within 3 months before pathological analysis, between 2015 and 2018. 37 patients with 43 observations (17 HCCs and 26 DNs) met the inclusion criteria. Two radiologists assessed major and ancillary imaging features for each liver observation and assigned a LI-RADS v2018 category in consensus. Estimates of diagnostic performance of major features, ancillary features, and LI-RADS categories were assessed based on their sensitivity, specificity, positive (PPV), and negative predictive values (NPV). RESULTS: Major features (nonrim arterial phase hyperenhancement, nonperipheral "washout", and enhancing "capsule") had a sensitivity of 94.1%, 88.2%, and 41.2%, and a specificity of 57.7%, 42.3%, and 88.5% for HCC, respectively. Ancillary features (hepatobiliary phase hypointensity, mild-moderate T2 hyperintensity, restricted diffusion, and fat in the lesion more than adjacent liver) had a sensitivity of 94.1%, 64.7%, 58.8%, and 11.8%, and a specificity of 26.9%, 61.5%, 65.4%, and 76.9% for HCC, respectively. The LR-5 category (determined by using major features only vs. the combination of major and ancillary features) had a sensitivity of 88.2% at both evaluations and a specificity of 76.9% and 80.8% for HCC, respectively. The combination of LR-4, LR-5 categories (determined by using major features only vs. the combination of major and ancillary features) had a sensitivity of 94.1% at both interpretations and a specificity of 65.4% and 26.9% for HCC, respectively. The use of ancillary features modified LI-RADS category in 25.6% of observations (11/43), predominantly upgraded from LR-3 to LR4 (10/11), increasing the proportion of low-grade DNs and high-grade DNs categorized as LR-4 (from 15.4% to 61.5% and from 7.7% to 46.1%, respectively). CONCLUSIONS: The added value of ancillary features in combination with major features is limited for the non-invasive diagnosis of small HCC; however, their use modifies the final category in a substantial proportion of observations from LR-3 to LR-4, thus allowing possible changes in the management of patients at risk for HCC.

Low molecular weight heparin as cause of liver injury: case report and literature review.

Low molecular weight heparins (LMWH) are a class of drugs including various molecules that inhibit predominantly the factor V of coagulation and are used in a wide range of clinical settings for the management of venous thromboembolism and acute coronary syndrome. Despite LMWH are considered safe and associated with a lower incidence of side effects compared to unfractioned heparin, it is worth considering that the use of LWMH can be associated with complications. Some of these, such as bleeding and thrombocytopenia, are well-known, whereas other ones are often underestimated leading to a diagnostic delay. In this case report, we describe a case of a 73-years-old man who recently started nadroparin for deep vein thrombosis presenting with acute hepatitis. The diagnostic workup of drug-induced liver injury (DILI) requires the exclusion of other causative agents and temporal association between the initiation of the culprit drug and hyper aminotransferasemia. This clinical case analyzes how to deal with a suspicion of DILI and consider LWMH as a potential cause of DILI, which requires a modification of the anticoagulant treatment.

Late reactivation of hepatitis B virus after rituximab-containing chemotherapy for mantle cell lymphoma: a case report.

BACKGROUND: Hepatitis B virus (HBV) reactivation is commonly observed in HBsAg-positive hematologic patients undergoing immunosuppressive chemotherapy. Recent guidelines recommend antiviral prophylaxis to be continued for up to 12 months after the discontinuation of the anticancer regimen. CASE PRESENTATION: We report a case of a patient who underwent antiviral prophylaxis for 26 months after the discontinuation of a rituximab-containing chemotherapy regimen for a lymphoma and was admitted in the infectious diseases department with a 3-day history of jaundice, itching, and dark urine. After excluding other possible causes of acute liver damage, HBV reactivation was suspected. HBV-DNA was 4497000 IU/mL. Following reintroduction of entecavir, we observed a steady decline of ALT, AST, bilirubin and HBV-DNA serum levels, with a rapid resolution of acute hepatitis and an improvement in clinical conditions; one year after the event of HBV reactivation and beginning of antiviral therapy, the patient was virologically suppressed. DISCUSSION: Our study demonstrates that the risk of HBV reactivation in HBsAg-positive patients with undetectable HBV-DNA can occur even after three years from the last administration of rituximab and several months after the withdrawal of prophylactic antiviral therapy in patients with hematological malignancies. This implies that a close monitoring of HBV-related markers including HBV-DNA must continue after the withdrawal of prophylactic NA therapy.

Gut microbiota and aging.

The hypothesis of an important role of gut microbiota in maintaining physiological state into the gastrointestinal (GI) system is supported by qualitative and quantitative alteration of the intestinal flora in a number of physiological and pathological condition as shown in several studies. The evidence of the inflammatory state alteration, highlighted in neurodegenerative diseases such as Parkinson's and Alzheimer's strongly recalls the microbiota disturbance, highly suggesting a link between the gastrointestinal system and cognitive functions. Given this perspective, looking at the mutual influence between microbiota products, inflammation mediators and immune system, the modulation of gut microbiota may help to facilitate a physiological and non-pathological aging process and, perhaps, to contrast the progression of degenerating mechanisms. Some studies have already characterized gut microbiota in elderly, with promising results. Future studies should be designed to better understand the correlation between the gut microbiota, the ageing process and degenerative diseases typical of the elderly.

Gut microbiome composition in lean patients with NASH is associated with liver damage independent of caloric intake: A prospective pilot study.

BACKGROUND AND AIM: The aim of the study was to compare the gut microbiomes from obese and lean patients with or without NASH to outline phenotypic differences. METHODS AND RESULTS: We performed a cross-sectional pilot study comprising biopsy-proven NASH patients grouped according to BMI. Microbiome DNA was extracted from stool samples, and PCR amplification was performed using primers for the V4 region of the 16S rRNA gene. The amplicons were sequenced using the Ion PGM Torrent platform, and data were analyzed using QIIME software. Macronutrient consumption was analyzed by a 7-day food record. Liver fibrosis ≥ F2 was associated with increased abundance of Lactobacilli (p = 0.0007). NASH patients showed differences in Faecalibacterium, Ruminococcus, Lactobacillus and Bifidobacterium abundance compared with the control group. Lean NASH patients had a 3-fold lower abundance of Faecalibacterium and Ruminococcus (p = 0.004), obese NASH patients were enriched in Lactobacilli (p = 0.002), and overweight NASH patients had reduced Bifidobacterium (p = 0.018). Moreover, lean NASH patients showed a deficiency in Lactobacillus compared with overweight and obese NASH patients. This group also appeared similar to the control group with regard to gut microbiome alpha diversity. Although there were qualitative differences between lean NASH and overweight/obese NASH, they were not statistically significant (p = 0.618). The study limitations included a small sample size, a food questionnaire that collected only qualitative and semi-quantitative data, and variations in group gender composition that may influence differences in FXR signaling, bile acids metabolism and the composition of gut microbiota. CONCLUSION: Our preliminary finding of a different pathogenetic process in lean NASH patients needs to be confirmed by larger studies, including those with patient populations stratified by sex and dietary habits.

A novel ultrasound-based vascular calcification score (CALCS) to detect subclinical atherosclerosis.

OBJECTIVE: To quantify non-coronary vascular calcifications (VC) in asymptomatic patients at low-intermediate cardiovascular risk by a new color Doppler ultrasound (DUS)-based score (the carotid, aortic, lower limbs calcium score, CALCs), and to correlate this score with classical parameters associated with cardiovascular risk [carotid intima media thickness (IMT), and arterial stiffness (AS)]. PATIENTS AND METHODS: All consecutive asymptomatic patients who underwent a screening DUS of non-coronary circulation were evaluated and patients at low-intermediate cardiovascular risk were selected according to Framingham risk score (FRS). Among them, we enrolled 70 patients with US evidence of VC and 71 age, sex and FRS matched controls. The presence of VC was correlated with classical markers of cardiovascular risk, such as AS and intima-media thickness (IMT). AS, expressed as pulse wave velocity (PWV) and arterial distensibility, carotid IMT and CALCs were measured for both groups. AS and c-IMT were assessed by a new Radio-Frequency (RF) DUS-based method. CALCs was generated by our previously described B-mode DUS-based method according to number/size of VC in 11 non-coronary segments (range 0-33). RESULTS: Patients with VC presented higher AS and IMT values than controls (PWV 8.34±0.98 m/s vs. 6.74±0.68 m/s, p<0.0001; arterial distensibility 267±12 mm vs. 315±65 mm, p=0.001; IMT 687±132 mm vs. 572±91 mm, p<0.0001). Mean CALCs of patients with VC was 8.41±7.78. CALCs were significantly correlated with c-IMT (p<0.0001; r=0.3), PWV (p<0.0001; r=0.4) and arterial distensibility (p=0.002; r=-0.1). CONCLUSIONS: DUS-based CALCs is highly correlated with other validated markers of subclinical atherosclerosis, such as c-IMT and AS. Our results demonstrated the ability of CALCs to identify individual predictive factors beyond the traditional risk factors by quantifying an interesting and novel step of the atherogenic process. Future studies on larger series and with adequate follow up are necessary to confirm these results and to evaluate the role of this new marker in monitoring calcific atherosclerosis progression.

Drug-induced liver injury 2017: the diagnosis is not easy but always to keep in mind.

A drug-induced liver injury (DILI) is defined as a liver injury caused by exposure to a drug or a non-infectious toxic agent with a variable degree of organ dysfunction. A better understanding of DILI epidemiology has been obtained in recent years with the institution of international registries in the United States and Europe. Despite the advances in the understanding and characterization of the phenomenon, DILI remains an exclusion diagnosis so, probability scores and the analysis of literature reports are useful tools in dealing with a suspected DILI. Idiosyncratic DILI can be considered a relatively rare event but it is one of the leading causes of acute liver failure. Thus, proper management is essential to avoid serious consequences. Here, we present an updated review of diagnostic and classification criteria of DILI. Prognostic tools, and principles of management and therapy have also been briefly discussed.

Liver transplantation for drug-induced acute liver failure.

OBJECTIVES: To summarize the different clinical features of drug-induced acute liver failure, the diagnostic work-up, conservative management and the prognostic scores currently used to list patients for liver transplantation. EVIDENCE AND INFORMATION SOURCES: The current review is based on an analysis of the current literature and the caseload experience of the Authors on this topic. STATE OF THE ART: Drug-induced liver injury is the leading cause of acute liver failure in the adult population in Western countries, with a transplant-free survival rate of less than 50%. Main subtypes include paracetamol and idiosyncratic drug-induced injury, which differ in epidemiology, clinical course, prognosis and conservative management. In cases of a high likelihood of death, urgent hepatic transplantation is indicated, but the decision whether and when to put a patient with drug-induced acute liver failure on the list for urgent liver transplant is extremely difficult and requires constant interdisciplinary exchange and continuous updating of the clinical picture. CONCLUSIONS: Intensive management should be done in a clinical tertiary referral center which has a specialized team of hepatologists and a liver transplant center.

Post-liver transplant intrahepatic cholestasis: etiology, clinical presentation, therapy.

Post-liver transplant intrahepatic cholestasis is consequent to the impairment of bile flow or formation. It may develop in the early (within 6 months) or in the late (more than 6 months) post-liver transplant period and different causes may be recognized according to the time elapsed from a liver transplant. The raise at various degrees of serum bilirubin, alkaline phosphatase, and gamma-glutamyl transpeptidase, with or without increased transaminases levels, are common hematochemical findings. Liver histology is helpful for diagnostic assessment, and sometimes crucial to differentiate among possible causes of cholestasis. Although timely treatment of underling conditions as well as supportive care may resolve post-liver transplant intrahepatic cholestasis, the risk of graft loss and retransplantation are remarkable. For this reason, post-liver transplant intrahepatic cholestasis should be managed in collaboration with the LT center, and treatment should be devolved to expert hepatologists.

New modalities of ultrasound-based intima-media thickness, arterial stiffness and non-coronary vascular calcifications detection to assess cardiovascular risk.

BACKGROUND: Carotid intima-media thickness (c-IMT), arterial stiffness (AS) and vascular calcification (VC) are now considered important new markers of atherosclerosis and have been associated with increased prevalence of cardiovascular events. An accurate, reproducible and easy detection of these parameters could increase the prognostic value of the traditional cardiovascular risk factors in many subjects at low and intermediate risk. Today, c-IMT and AS can be measured by ultrasound, while cardiac computed tomography is the gold standard to quantify coronary VC, although concern about the reproducibility of the former and the safety of the latter have been raised. Nevertheless, a safe and reliable method to quantify non-coronary (i.e., peripheral) VC has not been detected yet. AIM: To review the most innovative and accurate ultrasound-based modalities of c-IMT and AS detection and to describe a novel UltraSound-Based Carotid, Aortic and Lower limbs Calcification Score (USB-CALCs, simply named CALC), allowing to quantify peripheral calcifications. Finally, to propose a system for cardiovascular risk reclassification derived from the global evaluation of "Quality Intima-Media Thickness", "Quality Arterial Stiffness", and "CALC score" in addition to the Framingham score.

Biomarkers of low-grade inflammation in primary varicose veins of the lower limbs.

OBJECTIVE: To analyze serum biomarkers of CVD in selected patients with primary axial reflux of great saphenous vein in one or both lower limbs. PATIENTS AND METHODS: Ninety-six patients affected by uncomplicated varicose veins, were enrolled in the study. A unilateral, primary axial reflux in great saphenous veins was detected in 54 patients (U-CVD group) and a bilateral one in 42 (B-CVD group). Sixty-five age and sex-matched subjects without venous reflux were enrolled as controls. Mean venous pressure of both lower limbs at the distal great saphenous vein (mGSVP) and venous reflux were measured by continuous-wave Doppler ultrasound and echoduplex scanning, respectively. Reactive Oxygen Species (ROS), tissue Plasminogen Activator (t-PA) and its Inhibitor 1 (PAI-1) activities, Hematocrit (HTC), White Blood Cells (WBC), Neutrophyls (NEU), Platelets (PLT), Fibrinogen (FIB) and Blood Viscosity (BV) were assessed in blood samples drawn from the antecubital vein. RESULTS: B-CVD group showed higher fibrinogen values (p < 0.005) and higher mean venous pressure (0 < 0.0001) in comparison to controls, while U-CVD did not. No difference was found between both groups and controls for all the other parameters. CONCLUSIONS: Increased fibrinogen levels in patients with bilateral varicose veins may represent an early warning signal, as it could be associated to the long-term progression of chronic venous disease.

Something more to say about calcium homeostasis: the role of vitamin K2 in vascular calcification and osteoporosis.

BACKGROUND: Vascular calcification and osteoporosis share similar etiopathogenetic mechanisms. Vitamin K2 deficiency could be responsible of the so called "calcium paradox", that is the lack of calcium in the bone and its storage in the vessel wall. These events may have clinically relevant consequences, such as cardiovascular accidents, and bone fractures. AIM: To review the biological function of vitamin K2 metabolism, the main factors related to its deficiency and the consequent clinical significance. DISCUSSION: Vitamin K2 is essential for the function of several proteins, involved in the maintenance of the normal structure of arterial wall, osteoarticular system, teeth, and for the regulation of cell growth. It has been demonstrated to have a pivotal role in the inhibition of vascular foci of calcification, and in the regulation of calcium deposition in the bone. Vitamin K2 deficiency is often subclinic in a large part of healthy population. This deficiency is related to the interaction of various factors, such as the reduced dietary intake, the alteration of intestinal absorption or production, with a possible role of intestinal microbiota and the increased consumption at the vessel wall. CONCLUSIONS: Vitamin K2 deficiency has recently been recognized as a protagonist in the development of vascular calcification and osteoporosis. Data reported so far are promising and, dietary supplementation seems a useful tool to contrast these diseases. However, large studies or solid clinical correlations regarding vitamin K2 deficiency and its pathologic consequences are needed to confirm these preliminary experiences.