Publications by authors named "Luca Valenti"

256 Publications

Corrigendum to "Chromosome 3 cluster rs11385942 variant links complement activation with severe COVID-19" [J. Autoimmun. 117C (2020) 102595].

J Autoimmun 2021 Apr 30;120:102646. Epub 2021 Apr 30.

Universita ' degli Studi di Milano, Department of Pathophysiology and Transplantation, Milan, Italy; Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Internal Medicine and Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.jaut.2021.102646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086412PMC
April 2021

The rs599839 A>G Variant Disentangles Cardiovascular Risk and Hepatocellular Carcinoma in NAFLD Patients.

Cancers (Basel) 2021 Apr 8;13(8). Epub 2021 Apr 8.

General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy.

Background And Aims: Dyslipidemia and cardiovascular diseases (CVD) are comorbidities of nonalcoholic fatty liver disease (NAFLD), which ranges from steatosis to hepatocellular carcinoma (HCC). The rs599839 A>G variant, in the CELSR2-PSRC1-SORT1 gene cluster, has been associated CVD, but its impact on metabolic traits and on the severity liver damage in NAFLD has not been investigated yet.

Methods: We evaluated the effect of the rs599839 variant in 1426 NAFLD patients (Overall cohort) of whom 131 had HCC (NAFLD-HCC), in 500,000 individuals from the UK Biobank Cohort (UKBBC), and in 366 HCC samples from The Cancer Genome Atlas (TCGA). Hepatic PSRC1, SORT1 and CELSR2 expressions were evaluated by RNAseq ( = 125).

Results: The rs599839 variant was associated with reduced circulating LDL, carotid intima-media thickness, carotid plaques and hypertension ( < 0.05) in NAFLD patients and with protection against dyslipidemia in UKBBC. The minor G allele was associated with higher risk of HCC, independently of fibrosis severity (odds ratio (OR): 5.62; 95% c.i. 1.77-17.84, = 0.003), poor prognosis and advanced tumor stage ( < 0.05) in the overall cohort. Hepatic PSRC1, SORT1 and CELSR2 expressions were increased in NAFLD patients carrying the rs599839 variant ( < 0.0001). SORT1 mRNA levels negatively correlated with circulating lipids and with those of genes involved in lipoprotein turnover ( < 0.0001). Conversely, PSRC1 expression was positively related to that of genes implicated in cell proliferation ( < 0.0001). In TCGA, PSRC1 over-expression promoted more aggressive HCC development ( < 0.05).

Conclusions: In sum, the rs599839 A>G variant is associated with protection against dyslipidemia and CVD in NAFLD patients, but as one it might promote HCC development by modulating SORT1 and PSRC1 expressions which impact on lipid metabolism and cell proliferation, respectively.
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http://dx.doi.org/10.3390/cancers13081783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068289PMC
April 2021

A Role in the Genetic Predisposition to NAFLD-HCC?

Cancers (Basel) 2021 Mar 19;13(6). Epub 2021 Mar 19.

Translational and Clinical Research Institute, Faculty of Medical Sciences, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.

Obesity and non-alcoholic fatty liver disease (NAFLD) are contributing to the global rise in deaths from hepatocellular carcinoma (HCC). The pathogenesis of NAFLD-HCC is not well understood. The severity of hepatic steatosis, steatohepatitis and fibrosis are key pathogenic mechanisms, but animal studies suggest altered immune responses are also involved. Genetic studies have so far highlighted a major role of gene variants promoting fat deposition in the liver ( rs738409; rs58542926). Here, we have considered single-nucleotide polymorphisms (SNPs) in candidate immunoregulatory genes ( rs2596542; rs187115; rs7421861 and rs10204525), in 594 patients with NAFLD and 391 with NAFLD-HCC, from three European centres. Associations between age, body mass index, diabetes, cirrhosis and SNPs with HCC development were explored. and SNPs were associated with both progression to cirrhosis and NAFLD-HCC development, while SNPs were specifically associated with NAFLD-HCC risk, regardless of cirrhosis. rs7421861 was independently associated with NAFLD-HCC development, while rs10204525 acquired significance after adjusting for other risks, being most notable in the smaller numbers of women with NAFLD-HCC. The study highlights the potential impact of inter individual variation in immune tolerance induction in patients with NAFLD, both in the presence and absence of cirrhosis.
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http://dx.doi.org/10.3390/cancers13061412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003582PMC
March 2021

Emergency Lung Transplantation after COVID-19: Immunopathological Insights on Two Affected Patients.

Cells 2021 03 10;10(3). Epub 2021 Mar 10.

Division of Pathology, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy.

We herein characterize the immunopathological features of two Italian COVID-19 patients who underwent bilateral lung transplantation (bLTx). Removed lungs underwent histopathological evaluation. Gene expression profiling (GEP) for immune-related signatures was performed on lung specimens and SARS-CoV-2-stimulated peripheral blood mononuclear cells (PBMCs). Cytokine levels were measured on lungs, bronchoalveolar lavage fluids and in culture supernatants. Pathological assessment showed extensive lung damage with the pattern of proliferative to fibrotic phases, with diffuse alveolar damage mimicking usual interstitial pneumonia (UIP). Lungs' GEP revealed overexpression of pathogen recognition receptors, effector cytokines and chemokines, immune activation receptors and of the inflammasome components. Multiplex cytokine analysis confirmed a proinflammatory state, with high levels of monocyte/macrophage chemotactic and activating factors and of IL-6 and TNF-α. A similar profile was observed in SARS-CoV-2-stimulated PBMCs collected 7 days after transplant. The pattern of tissue damage observed in the lungs suggests that this may represent the output of protracted disease, resembling a diffuse UIP-like picture. The molecular immune profiling supports the paradigm of a persistent proinflammatory state and sustained humoral immunity, conditions that are maintained despite the iatrogenic immunosuppression.
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http://dx.doi.org/10.3390/cells10030611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999589PMC
March 2021

Ceruloplasmin gene variants are associated with hyperferritinemia and increased liver iron in patients with NAFLD.

J Hepatol 2021 Mar 24. Epub 2021 Mar 24.

Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy; Translational Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Policlinico di Milano, Milan, Italy. Electronic address:

Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is a multifactorial disorder resulting from genetic and environmental factors. Hyperferritinemia has been associated with increased hepatic iron stores and worse outcomes in NAFLD patients. The aim of this study was to evaluate the prevalence of variants of iron-related genes and their association with hyperferritinemia, hepatic iron stores and liver disease severity in NAFLD patients.

Methods: From a cohort of 328 subjects with histological NAFLD, 23 patients with ferritin >750 ng/ml and positive iron staining, and 25 controls with normal ferritin and negative iron staining were selected. Patients with increased transferrin saturation, anemia, inflammation, and beta-thalassemia trait, HFE genotype at risk of iron overload and Ferroportin mutations were excluded. A panel of 32 iron genes was re-sequenced. Literature and in silico predictions were employed for prioritization of pathogenic mutations.

Results: Hyperferritinemia patients had a higher prevalence of potential pathogenic rare variants (73.9% vs 20%, p=0.0002) associated with higher iron stores and more severe liver fibrosis (p<0.05). Ceruloplasmin was the most mutated gene and its variants were independently associated with hyperferritinemia, hepatic siderosis, and more severe liver fibrosis (p<0.05). In the overall cohort, ceruloplasmin variants were independently associated with hyperferritinemia (adjusted OR 5.99, 1.83-19.60; p=0.0009).

Conclusions: Variants in non-HFE iron genes, particularly Ceruloplasmin, are associated with hyperferritinemia and increased hepatic iron stores in patients with NAFLD. Carriers of such variants have a more severe liver fibrosis, suggesting that genetic predisposition to hepatic iron deposition may translate into liver disease.

Lay Summary: Nonalcoholic fatty liver disease (NAFLD) is a common disease with potential evolution to cirrhosis and liver cancer. Increased levels of serum ferritin are often detected in NAFLD patients and have been associated with altered iron metabolism and worse patient outcomes. We found that variants of genes related to iron metabolism, particularly Ceruloplasmin, are associated with high ferritin levels, hepatic iron deposition and more severe liver disease in Italian NAFLD patients.
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http://dx.doi.org/10.1016/j.jhep.2021.03.014DOI Listing
March 2021

Age-dependent impact of the major common genetic risk factor for COVID-19 on severity and mortality.

medRxiv 2021 Mar 12. Epub 2021 Mar 12.

Background: There is considerable variability in COVID-19 outcomes amongst younger adults-and some of this variation may be due to genetic predisposition. We characterized the clinical implications of the major genetic risk factor for COVID-19 severity, and its age-dependent effect, using individual-level data in a large international multi-centre consortium.

Method: The major common COVID-19 genetic risk factor is a chromosome 3 locus, tagged by the marker rs10490770. We combined individual level data for 13,424 COVID-19 positive patients (N=6,689 hospitalized) from 17 cohorts in nine countries to assess the association of this genetic marker with mortality, COVID-19-related complications and laboratory values. We next examined if the magnitude of these associations varied by age and were independent from known clinical COVID-19 risk factors.

Findings: We found that rs10490770 risk allele carriers experienced an increased risk of all-cause mortality (hazard ratio [HR] 1·4, 95% confidence interval [CI] 1·2-1·6) and COVID-19 related mortality (HR 1·5, 95%CI 1·3-1·8). Risk allele carriers had increased odds of several COVID-19 complications: severe respiratory failure (odds ratio [OR] 2·0, 95%CI 1·6-2·6), venous thromboembolism (OR 1·7, 95%CI 1·2-2·4), and hepatic injury (OR 1·6, 95%CI 1·2-2·0). Risk allele carriers ≤ 60 years had higher odds of death or severe respiratory failure (OR 2·6, 95%CI 1·8-3·9) compared to those > 60 years OR 1·5 (95%CI 1·3-1·9, interaction p-value=0·04). Amongst individuals ≤ 60 years who died or experienced severe respiratory COVID-19 outcome, we found that 31·8% (95%CI 27·6-36·2) were risk variant carriers, compared to 13·9% (95%CI 12·6-15·2%) of those not experiencing these outcomes. Prediction of death or severe respiratory failure among those ≤ 60 years improved when including the risk allele (AUC 0·82 vs 0·84, p=0·016) and the prediction ability of rs10490770 risk allele was similar to, or better than, most established clinical risk factors.

Interpretation: The major common COVID-19 risk locus on chromosome 3 is associated with increased risks of morbidity and mortality-and these are more pronounced amongst individuals ≤ 60 years. The effect on COVID-19 severity was similar to, or larger than most established risk factors, suggesting potential implications for clinical risk management.

Funding: Funding was obtained by each of the participating cohorts individually.
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http://dx.doi.org/10.1101/2021.03.07.21252875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987046PMC
March 2021

Adipocyte PHLPP2 inhibition prevents obesity-induced fatty liver.

Nat Commun 2021 03 23;12(1):1822. Epub 2021 Mar 23.

Department of Medicine, Columbia University, New York, NY, USA.

Increased adiposity confers risk for systemic insulin resistance and type 2 diabetes (T2D), but mechanisms underlying this pathogenic inter-organ crosstalk are incompletely understood. We find PHLPP2 (PH domain and leucine rich repeat protein phosphatase 2), recently identified as the Akt Ser473 phosphatase, to be increased in adipocytes from obese mice. To identify the functional consequence of increased adipocyte PHLPP2 in obese mice, we generated adipocyte-specific PHLPP2 knockout (A-PHLPP2) mice. A-PHLPP2 mice show normal adiposity and glucose metabolism when fed a normal chow diet, but reduced adiposity and improved whole-body glucose tolerance as compared to Cre- controls with high-fat diet (HFD) feeding. Notably, HFD-fed A-PHLPP2 mice show increased HSL phosphorylation, leading to increased lipolysis in vitro and in vivo. Mobilized adipocyte fatty acids are oxidized, leading to increased peroxisome proliferator-activated receptor alpha (PPARα)-dependent adiponectin secretion, which in turn increases hepatic fatty acid oxidation to ameliorate obesity-induced fatty liver. Consistently, adipose PHLPP2 expression is negatively correlated with serum adiponectin levels in obese humans. Overall, these data implicate an adipocyte PHLPP2-HSL-PPARα signaling axis to regulate systemic glucose and lipid homeostasis, and suggest that excess adipocyte PHLPP2 explains decreased adiponectin secretion and downstream metabolic consequence in obesity.
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http://dx.doi.org/10.1038/s41467-021-22106-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988046PMC
March 2021

Reply to: "Polygenic risk score: A promising predictor for hepatocellular carcinoma in the population with non-alcoholic fatty liver disease".

J Hepatol 2021 Mar 5. Epub 2021 Mar 5.

Precision Medicine - Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, via F Sforza 35, 20122, Milan, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2021.02.030DOI Listing
March 2021

Impact of SARS-CoV-2 infection on the recovery of peripheral blood mononuclear cells by density gradient.

Sci Rep 2021 03 1;11(1):4904. Epub 2021 Mar 1.

Department of Transfusion Medicine and Hematology, Milano Cord Blood Bank, Processing Facility and Biobank POLI-MI, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza, 35, 20122, Milan, Italy.

SARS-CoV-2 virus infection is responsible for coronavirus disease (COVID-19), which is characterised by a hyperinflammatory response that plays a major role in determining the respiratory and immune-mediated complications of this condition. While isolating peripheral blood mononuclear cells (PBMCs) from whole blood of COVID-19 patients by density gradient centrifugation, we noticed some changes in the floating properties and in the sedimentation of the cells on density medium. Investigating this further, we found that in early phase COVID-19 patients, characterised by reduced circulating lymphocytes and monocytes, the PBMC fraction contained surprisingly high levels of neutrophils. Furthermore, the neutrophil population exhibited alterations in the cell size and in the internal complexity, consistent with the presence of low density neutrophils (LDNs) and immature forms, which may explain the shift seen in the floating abilities and that may be predictive of the severity of the disease. The percentage of this subset of neutrophils found in the PBMC band was rather spread (35.4 ± 27.2%, with a median 28.8% and IQR 11.6-56.1, Welch's t-test early phase COVID-19 versus blood donor healthy controls P < 0.0001). Results confirm the presence of an increased number of LDNs in patients with early stage COVID-19, which correlates with disease severity and may be recovered by centrifugation on a density gradient together with PBMCs.
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http://dx.doi.org/10.1038/s41598-021-83950-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921094PMC
March 2021

The KLB rs17618244 gene variant is associated with fibrosing MAFLD by promoting hepatic stellate cell activation.

EBioMedicine 2021 Mar 25;65:103249. Epub 2021 Feb 25.

General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pad. Granelli, via F Sforza 35, Milan 20122, Italy. Electronic address:

Background: The rs17618244 G>A β-Klotho (KLB) variant has been associated with increased risk of ballooning and inflammation in pediatric patients with metabolic associated fatty liver disease (MAFLD), by reducing KLB expression. In hepatocytes, KLB downregulation induced fat accumulation and the expression of inflammatory and lipotoxic genes. We aimed to examine firstly the impact of the KLB rs17618244 variation on liver damage in adult patients with MAFLD and secondly its effect on hepatic stellate cells (HSCs) activation.

Methods: The impact of the KLB rs17618244 variant on histological liver damage was surveyed in a retrospective cohort of 1111 adult patients with MAFLD. Subgroup analysis was performed according to the presence of obesity (BMI>35; n = 708). Immortalized HSCs (LX-2) were transfected with the KLB wild type (LX-2_KLBwt), or with the mutant one carrying the rs17618244 (LX-2_KLBmut).

Findings: At ordinal regression analysis the KLB rs17618244 variant was associated with hepatic fibrosis (OR 1.23, 95% C.I.1.004-1.51; p = 0.04), but not with steatosis, inflammation and ballooning. By stratifying patients according to the presence of obesity, the KLB A allele was further associated with lobular inflammation (OR 1.32, 95% C.I.1.02-1.72; p = 0.03) and cirrhosis (OR 2.51, 95% C.I.1.23-5.05; p = 0.01) Moreover, hepatic KLB expression correlated with that of fibrogenic genes. LX-2_KLBmut cells showed reduced KLB protein levels paralleled by an induction of pro-fibrogenic genes and enhanced proliferative rate.

Interpretation: The KLB rs17618244 variant is associated with hepatic fibrosis, inflammation and cirrhosis mainly in obese patients with MAFLD and HSCs which carry this mutation are highly proliferative and acquire a myofibroblast-like phenotype.

Funding: Ricerca Finalizzata Ministero della Salute GR-2019-12,370,172 (NP), Ricerca Corrente Fondazione IRCCS Cà Granda (PD and ALF), Ricerca Finalizzata Ministero della Salute RF-2013-02,358,319 (ALF), and Ricerca Corrente and 5 × 1000 Ministero della Salute (AA).
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http://dx.doi.org/10.1016/j.ebiom.2021.103249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921469PMC
March 2021

Variants in PCSK7, PNPLA3 and TM6SF2 are risk factors for the development of cirrhosis in hereditary haemochromatosis.

Aliment Pharmacol Ther 2021 04 10;53(7):830-843. Epub 2021 Feb 10.

London, UK.

Background: Cirrhosis develops in <10% of individuals homozygous for the C282Y variant in the homeostatic iron regulator (HFE) gene. Carriage of PCSK7:rs236918 is associated with an increased risk of cirrhosis in this population.

Aim: To determine if genetic variants significantly associated with the risk of alcohol- and NAFLD-related cirrhosis also modulate the cirrhosis risk in C282Y homozygotes.

Methods: Variants in PCSK7, PNPLA3, TM6SF2, MBOAT7 and HSD17B13 were genotyped in 1319 C282Y homozygotes, from six European countries, of whom 171 (13.0%) had cirrhosis. Genotypic and allelic associations with the risk for developing cirrhosis were assessed, adjusting for age and sex. Fixed effects meta-analyses of the adjusted summary data for each country were performed. Post hoc association testing was undertaken in the 131 (76.6%) cases and 299 (26.0%) controls with available liver histology.

Results: Significant associations were observed between PCSK7:rs236918 (OR = 1.52 [95% CI 1.06-2.19]; P = 0.022; I  = 0%); PNPLA3:rs738409 (OR = 1.60 [95% CI 1.22-2.11]; P = 7.37 × 10 ; I  = 45.5%) and TM6SF2:rs58542926 (OR = 1.94 [95% CI 1.28-2.95]; P = 1.86 × 10 ; I  = 0%) and the cirrhosis risk in C282Y homozygotes. These findings remained significant in the subpopulation with available liver histology. The population-attributable fractions were 5.6% for PCSK7:rs236918, 13.8% for PNPLA3:rs738409, 6.5% for TM6SF2:rs58542926 and 24.0% for carriage of all three variants combined.

Conclusions: The risk of cirrhosis associated with carriage of PCSK7:rs236918 was confirmed in this much larger population of C282Y homozygotes. In addition, PNPLA3:rs738409 and TM6SF2:rs58542926 were established as significant additional risk factors. More detailed genetic testing of C282Y homozygotes would allow risk stratification and help guide future management.
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http://dx.doi.org/10.1111/apt.16252DOI Listing
April 2021

Caucasian lean subjects with non-alcoholic fatty liver disease share long-term prognosis of non-lean: time for reappraisal of BMI-driven approach?

Gut 2021 Feb 4. Epub 2021 Feb 4.

UCM Digestive Diseases and SeLiver Group, Virgen del Rocio University Hospital, Institute of Biomedicine of Seville, University of Seville, Seville, Spain.

Objective: The full phenotypic expression of non-alcoholic fatty liver disease (NAFLD) in lean subjects is incompletely characterised. We aimed to investigate prevalence, characteristics and long-term prognosis of Caucasian lean subjects with NAFLD.

Design: The study cohort comprises 1339 biopsy-proven NAFLD subjects from four countries (Italy, UK, Spain and Australia), stratified into lean and non-lean (body mass index (BMI)
Results: Lean patients represented 14.4% of the cohort and were predominantly of Italian origin (89%). They had less severe histological disease (lean vs non-lean: non-alcoholic steatohepatitis 54.1% vs 71.2% p<0.001; advanced fibrosis 10.1% vs 25.2% p<0.001), lower prevalence of diabetes (9.2% vs 31.4%, p<0.001), but no significant differences in the prevalence of the I148M variant (p=0.57). During a median follow-up of 94 months (>10 483 person-years), 4.7% of lean vs 7.7% of non-lean patients reported liver-related events (p=0.37). No difference in survival was observed compared with non-lean NAFLD (p=0.069).

Conclusions: Caucasian lean subjects with NAFLD may progress to advanced liver disease, develop metabolic comorbidities and experience cardiovascular disease (CVD) as well as liver-related mortality, independent of longitudinal progression to obesity and genotype. These patients represent one end of a wide spectrum of phenotypic expression of NAFLD where the disease manifests at lower overall BMI thresholds.

Lay Summary: NAFLD may affect and progress in both obese and lean individuals. Lean subjects are predominantly males, have a younger age at diagnosis and are more prevalent in some geographic areas. During the follow-up, lean subjects can develop hepatic and extrahepatic disease, including metabolic comorbidities, in the absence of weight gain. These patients represent one end of a wide spectrum of phenotypic expression of NAFLD.
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http://dx.doi.org/10.1136/gutjnl-2020-322564DOI Listing
February 2021

SARS-CoV-2 seroprevalence trends in healthy blood donors during the COVID-19 outbreak in Milan.

Blood Transfus 2021 05 3;19(3):181-189. Epub 2021 Feb 3.

Department of Transfusion Medicine and Haematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Background: The Milan metropolitan area in Northern Italy was among the most severely hit by the SARS-CoV-2 outbreak. The aim of this study was to examine the seroprevalence trends of SARS-CoV-2 in healthy asymptomatic adults, and the risk factors and laboratory correlates of positive tests.

Materials And Methods: We conducted a cross-sectional study in a random sample of blood donors, who were asymptomatic at the time of evaluation, at the beginning of the first phase (February 24 to April 8 2020; n=789). Presence of IgM/IgG antibodies against the SARS-CoV-2-Nucleocapsid protein was assessed by a lateral flow immunoassay.

Results: The test had a 100/98.3 sensitivity/specificity (n=32/120 positive/negative controls, respectively), and the IgG test was validated in a subset by an independent ELISA against the Spike protein (n=34, p<0.001). At the start of the outbreak, the overall adjusted seroprevalence of SARS-CoV-2 was 2.7% (95% CI: 0.3-6%; p<0.0001 vs 120 historical controls). During the study period, characterised by a gradual implementation of social distancing measures, there was a progressive increase in the adjusted seroprevalence to 5.2% (95% CI: 2.4-9.0; 4.5%, 95% CI: 0.9-9.2% according to a Bayesian estimate) due to a rise in IgG reactivity to 5% (95% CI: 2.8-8.2; p=0.004 for trend), but there was no increase in IgM (p=not significant). At multivariate logistic regression analysis, IgG reactivity was more frequent in younger individuals (p=0.043), while IgM reactivity was more frequent in individuals aged >45 years (p=0.002).

Discussion: SARS-CoV-2 infection was already circulating in Milan at the start of the outbreak. The pattern of IgM/IgG reactivity was influenced by age: IgM was more frequently detected in participants aged >45 years. By the end of April, 2.4-9.0% of healthy adults had evidence of seroconversion.
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http://dx.doi.org/10.2450/2021.0324-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092034PMC
May 2021

Diagnosis and Management of Autoimmune Hemolytic Anemia in Patients with Liver and Bowel Disorders.

J Clin Med 2021 Jan 22;10(3). Epub 2021 Jan 22.

Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.

Anemia is a common feature of liver and bowel diseases. Although the main causes of anemia in these conditions are represented by gastrointestinal bleeding and iron deficiency, autoimmune hemolytic anemia should be considered in the differential diagnosis. Due to the epidemiological association, autoimmune hemolytic anemia should particularly be suspected in patients affected by inflammatory and autoimmune diseases, such as autoimmune or acute viral hepatitis, primary biliary cholangitis, and inflammatory bowel disease. In the presence of biochemical indices of hemolysis, the direct antiglobulin test can detect the presence of warm or cold reacting antibodies, allowing for a prompt treatment. Drug-induced, immune-mediated hemolytic anemia should be ruled out. On the other hand, the choice of treatment should consider possible adverse events related to the underlying conditions. Given the adverse impact of anemia on clinical outcomes, maintaining a high clinical suspicion to reach a prompt diagnosis is the key to establishing an adequate treatment.
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http://dx.doi.org/10.3390/jcm10030423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865399PMC
January 2021

Chromosome 3 cluster rs11385942 variant links complement activation with severe COVID-19.

J Autoimmun 2021 02 9;117:102595. Epub 2021 Jan 9.

Università degli Studi di Milano, Department of Pathophysiology and Transplantation, Milan, Italy; Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Internal Medicine and Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy. Electronic address:

Background: Genetic variation at a multigene cluster at chromosome 3p21.31 and the ABO blood group have been associated with the risk of developing severe COVID-19, but the mechanism remains unclear. Complement activation has been associated with COVID-19 severity.

Objective: The aim of this study was to examine whether chromosome 3p21.31 and the ABO variants are linked to the activation of the complement cascade in COVID-19 patients.

Methods: We considered 72 unrelated European hospitalized patients with genetic data and evaluation of circulating C5a and soluble terminal complement complex C5b-9 (SC5b-9). Twenty-six (36.1%) patients carried the rs11385942 G>GA variant and 44 (66.1%) non-O blood group associated with increased risk of severe COVID-19.

Results: C5a and SC5-b9 plasma levels were higher in rs11385949 GA carriers than in non-carriers (P = 0.041 and P = 0.012, respectively), while C5a levels were higher in non-O group than in O group patients (P = 0.019). The association between rs11385949 and SC5b-9 remained significant after adjustment for ABO and disease severity (P = 0.004) and further correction for C5a (P = 0.018). There was a direct relationship between upper airways viral load and SC5b-9 in carriers of the rs11385949 risk allele (P = 0.032), which was not observed in non-carriers.

Conclusions: The rs11385949 G>GA variant, tagging the chromosome 3 gene cluster variation and predisposing to severe COVID-19, is associated with enhanced complement activation, both with C5a and terminal complement complex, while non-O blood group with C5a levels. These findings provide a link between genetic susceptibility to more severe COVID-19 and complement activation.
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http://dx.doi.org/10.1016/j.jaut.2021.102595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796659PMC
February 2021

Should individuals who have been cured of hepatitis C virus and their partners be allowed to donate blood?

Lancet Haematol 2021 01 22;8(1):e8-e10. Epub 2020 Dec 22.

Department of Transfusion Medicine and Hematology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan 20122, Italy. Electronic address:

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http://dx.doi.org/10.1016/S2352-3026(20)30402-6DOI Listing
January 2021

Exome-Wide Association Study on Alanine Aminotransferase Identifies Sequence Variants in the GPAM and APOE Associated With Fatty Liver Disease.

Gastroenterology 2021 Apr 6;160(5):1634-1646.e7. Epub 2021 Feb 6.

Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden; Clinical Nutrition Unit, Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy; Cardiology Department, Sahlgrenska University Hospital, Gothenburg, Sweden. Electronic address:

Background & Aims: Fatty liver disease (FLD) is a growing epidemic that is expected to be the leading cause of end-stage liver disease within the next decade. Both environmental and genetic factors contribute to the susceptibility of FLD. Several genetic variants contributing to FLD have been identified in exome-wide association studies. However, there is still a missing hereditability indicating that other genetic variants are yet to be discovered.

Methods: To find genes involved in FLD, we first examined the association of missense and nonsense variants with alanine aminotransferase at an exome-wide level in 425,671 participants from the UK Biobank. We then validated genetic variants with liver fat content in 8930 participants in whom liver fat measurement was available, and replicated 2 genetic variants in 3 independent cohorts comprising 2621 individuals with available liver biopsy.

Results: We identified 190 genetic variants independently associated with alanine aminotransferase after correcting for multiple testing with Bonferroni method. The majority of these variants were not previously associated with this trait. Among those associated, there was a striking enrichment of genetic variants influencing lipid metabolism. We identified the variants rs2792751 in GPAM/GPAT1, the gene encoding glycerol-3-phosphate acyltransferase, mitochondrial, and rs429358 in APOE, the gene encoding apolipoprotein E, as robustly associated with liver fat content and liver disease after adjusting for multiple testing. Both genes affect lipid metabolism in the liver.

Conclusions: We identified 2 novel genetic variants in GPAM and APOE that are robustly associated with steatosis and liver damage. These findings may help to better elucidate the genetic susceptibility to FLD onset and progression.
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http://dx.doi.org/10.1053/j.gastro.2020.12.023DOI Listing
April 2021

Non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores.

J Hepatol 2021 Apr 25;74(4):775-782. Epub 2020 Nov 25.

Translational Medicine - Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy. Electronic address:

Background & Aims: Hepatocellular carcinoma (HCC) risk stratification in individuals with dysmetabolism is a major unmet need. Genetic predisposition contributes to non-alcoholic fatty liver disease (NAFLD). We aimed to exploit robust polygenic risk scores (PRS) that can be evaluated in the clinic to gain insight into the causal relationship between NAFLD and HCC, and to improve HCC risk stratification.

Methods: We examined at-risk individuals (NAFLD cohort, n = 2,566; 226 with HCC; and a replication cohort of 427 German patients with NAFLD) and the general population (UK Biobank [UKBB] cohort, n = 364,048; 202 with HCC). Variants in PNPLA3-TM6SF2-GCKR-MBOAT7 were combined in a hepatic fat PRS (PRS-HFC), and then adjusted for HSD17B13 (PRS-5).

Results: In the NAFLD cohort, the adjusted impact of genetic risk variants on HCC was proportional to the predisposition to fatty liver (p = 0.002) with some heterogeneity in the effect. PRS predicted HCC more robustly than single variants (p <10). The association between PRS and HCC was mainly mediated through severe fibrosis, but was independent of fibrosis in clinically relevant subgroups, and was also observed in those without severe fibrosis (p <0.05). In the UKBB cohort, PRS predicted HCC independently of classical risk factors and cirrhosis (p <10). In the NAFLD cohort, we identified high PRS cut-offs (≥0.532/0.495 for PRS-HFC/PRS-5) that in the UKBB cohort detected HCC with ~90% specificity but limited sensitivity; PRS predicted HCC both in individuals with (p <10) and without cirrhosis (p <0.05).

Conclusions: Our results are consistent with a causal relationship between hepatic fat and HCC. PRS improved the accuracy of HCC detection and may help stratify HCC risk in individuals with dysmetabolism, including those without severe liver fibrosis. Further studies are needed to validate our findings.

Lay Summary: By analyzing variations in genes that contribute to fatty liver disease, we developed two risk scores to help predict liver cancer in individuals with obesity-related metabolic complications. These risk scores can be easily tested in the clinic. We showed that the risk scores helped to identify the risk of liver cancer both in high-risk individuals and in the general population.
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http://dx.doi.org/10.1016/j.jhep.2020.11.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987554PMC
April 2021

Complement activation and endothelial perturbation parallel COVID-19 severity and activity.

J Autoimmun 2021 01 29;116:102560. Epub 2020 Oct 29.

Università degli Studi di Milano, Department of Pathophysiology and Transplantation, Milan, Italy; Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Internal Medicine and Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy.

Background: Animal models and few clinical reports suggest the involvement of the complement system in the onset of severe manifestations of coronavirus disease-2019 (COVID-19). However, complement contribution to endotheliopathy and hypercoagulability has not been elucidated yet.

Objective: To evaluate the association among complement activation, endothelial damage and disease severity or activity in COVID-19 patients.

Methods: In this single-centre cohort study, 148 patients with COVID-19 of different severity were evaluated upon hospital admission and 30 days later. Markers of complement activation (SC5b-9 and C5a) and endothelial perturbation (von Willebrand factor [vWF], tissue-type plasminogen activator [t-PA], plasminogen activator inhibitor-1 [PAI-1], soluble thrombomodulin [sTM], and soluble endothelial selectin [sE-selectin]) were measured in plasma.

Results: The patients had high plasma levels of SC5b-9 and C5a (p = 0.0001 for both) and vWF, t-PA and PAI-1 (p = 0.0001 for all). Their SC5b-9 levels correlated with those of vWF (r = 0.517, p = 0.0001) and paralleled disease severity (severe vs mild p = 0.0001, severe vs moderate p = 0.026 and moderate vs mild p = 0.001). The levels of sE-selectin were significantly increased only in the patients with severe disease. After 30 days, plasma SC5b-9, C5a and vWF levels had significantly decreased (p = 0.0001 for all), and 43% of the evaluated patients had normal levels.

Conclusions: Complement activation is boosted during the progression of COVID-19 and dampened during remission, thus indicating its role in the pathophysiology of the disease. The association between complement activation and the biomarkers of endothelial damage suggests that complement may contribute to tissue injury and could be the target of specific therapy.
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http://dx.doi.org/10.1016/j.jaut.2020.102560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598768PMC
January 2021

Human and molecular genetics shed lights on fatty liver disease and diabetes conundrum.

Endocrinol Diabetes Metab 2020 Oct 4;3(4):e00179. Epub 2020 Sep 4.

Department of Molecular and Clinical Medicine Sahlgrenska Academy University of Gothenburg Gothenburg Sweden.

The causal role of abdominal overweight/obesity, insulin resistance and type 2 diabetes (T2D) on the risk of fatty liver disease (FLD) has robustly been proven. A consensus of experts has recently proposed the novel definition of 'metabolic dysfunction-associated fatty liver disease, MAFLD' instead of 'nonalcoholic fatty liver disease, NAFLD', emphasizing the central role of dysmetabolism in the disease pathogenesis. Conversely, a direct and independent contribution of FLD on risk of developing T2D is still a controversial topic. When dealing with FLD as a potential risk factor for T2D, it is straightforward to think of hepatic insulin resistance as the most relevant underlying mechanism. Emerging evidence supports genetic determinants of FLD (eg ) as determinants of insulin resistance and T2D. However, recent studies highlighted that the key molecular mechanism of dysmetabolism is not fat accumulation but the degree of hepatic fibrosis (excess liver fat content-lipotoxicity), leading to reduced insulin clearance, insulin resistance and T2D. A consequence of these findings is that drugs that will ameliorate liver fat accumulation and fibrosis in principle may also exert a beneficial effect on insulin resistance and risk of T2D in individuals with FLD. Finally, initial findings show that these genetic factors might be directly implicated in modulating pancreatic beta-cell function, although future studies are needed to fully understand this relationship.
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http://dx.doi.org/10.1002/edm2.179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576307PMC
October 2020

Genetic insight into COVID-19-related liver injury.

Liver Int 2021 01 3;41(1):227-229. Epub 2020 Nov 3.

Translational Medicine - Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

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http://dx.doi.org/10.1111/liv.14708DOI Listing
January 2021

PCSK9 rs11591147 R46L loss-of-function variant protects against liver damage in individuals with NAFLD.

Liver Int 2021 02 2;41(2):321-332. Epub 2020 Nov 2.

Sezione di Gastroenterologia e Epatologia, PROMISE, University of Palermo, Palermo, Italy.

Background And Aims: The proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in cholesterol homeostasis, and its inhibition represents an effective therapy to lower low-density lipoprotein cholesterol (LDL-C) levels. In this study, we examined the impact of the PCSK9 rs11591147 loss-of-function (LOF) variant on liver damage in a multicenter collection of patients at risk of nonalcoholic steatohepatitis (NASH), in clinical samples and experimental models.

Methods: We considered 1874 consecutive individuals at risk of NASH as determined by histology. The SNP rs11591147, encoding for the p.R46L variant of PCSK9, was genotyped by TaqMan assays. We also evaluated 1) PCSK9 mRNA hepatic expression in human liver, and 2) the impact of a NASH-inducing diet in mice with hepatic overexpression of human PCSK9.

Results: Carriers of PCSK9 rs11591147 had lower circulating LDL-C levels and were protected against nonalcoholic fatty liver disease (NAFLD) (OR: 0.42; 95% CI: 0.22-0.81; P = .01), NASH (OR: 0.48; 95% CI: 0.26-0.87; P = .01) and more severe fibrosis (OR: 0.55; 95% CI: 0.32-0.94; P = .03) independently of clinical, metabolic and genetic confounding factors. PCSK9 hepatic expression was directly correlated with liver steatosis (P = .03). Finally, liver-specific overexpression of human PCSK9 in male mice drives NAFLD and fibrosis upon a dietary challenge.

Conclusions: In individuals at risk of NASH, PCSK9 was induced with hepatic fat accumulation and PCSK9 rs11591147 LOF variant was protective against liver steatosis, NASH and fibrosis, suggesting that PCSK9 inhibition may be a new therapeutic strategy to treat NASH.
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http://dx.doi.org/10.1111/liv.14711DOI Listing
February 2021

The European NAFLD Registry: A real-world longitudinal cohort study of nonalcoholic fatty liver disease.

Contemp Clin Trials 2020 11 9;98:106175. Epub 2020 Oct 9.

Sorbonne Université, Institute of Cardiometabolism and Nutrition, Pitié-Salpêtrière Hospital, Paris, France.

Non-Alcoholic Fatty Liver Disease (NAFLD), a progressive liver disease that is closely associated with obesity, type 2 diabetes, hypertension and dyslipidaemia, represents an increasing global public health challenge. There is significant variability in the disease course: the majority exhibit only fat accumulation in the liver but a significant minority develop a necroinflammatory form of the disease (non-alcoholic steatohepatitis, NASH) that may progress to cirrhosis and hepatocellular carcinoma. At present our understanding of pathogenesis, disease natural history and long-term outcomes remain incomplete. There is a need for large, well characterised patient cohorts that may be used to address these knowledge gaps and to support the development of better biomarkers and novel therapies. The European NAFLD Registry is an international, prospectively recruited observational cohort study that aims to establish a large, highly-phenotyped patient cohort and linked bioresource. Here we describe the infrastructure, data management and monitoring plans, and the standard operating procedures implemented to ensure the timely and systematic collection of high-quality data and samples. Already recruiting subjects at secondary/tertiary care centres across Europe, the Registry is supporting the European Union IMI2-funded LITMUS 'Liver Investigation: Testing Marker Utility in Steatohepatitis' consortium, which is a major international effort to robustly validate biomarkers that diagnose, risk stratify and/or monitor NAFLD progression and liver fibrosis stage. The European NAFLD Registry has the demonstrable capacity to support research and biomarker development at scale and pace.
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http://dx.doi.org/10.1016/j.cct.2020.106175DOI Listing
November 2020

Association of ABO blood group and secretor phenotype with severe COVID-19.

Transfusion 2020 12 19;60(12):3067-3070. Epub 2020 Oct 19.

Transfusion Medicine and Hematology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.

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http://dx.doi.org/10.1111/trf.16130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675339PMC
December 2020

Red blood cell morphology in patients with COVID-19-related anaemia.

Blood Transfus 2021 01 18;19(1):34-36. Epub 2020 Sep 18.

Department of Transfusion Medicine and Haematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico", Milan, Italy.

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http://dx.doi.org/10.2450/2020.0242-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850925PMC
January 2021

MAFLD vs NAFLD: Let the contest begin!

Liver Int 2020 09;40(9):2079-2081

Translational Medicine - Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

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http://dx.doi.org/10.1111/liv.14620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510483PMC
September 2020

rs641738C>T near MBOAT7 is associated with liver fat, ALT and fibrosis in NAFLD: A meta-analysis.

J Hepatol 2021 Jan 31;74(1):20-30. Epub 2020 Aug 31.

MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, UK.

Background & Aims: A common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in NAFLD; however, these findings have not been consistently replicated in the literature. We aimed to establish whether rs641738C>T is a risk factor across the spectrum of NAFLD and to characterise its role in the regulation of related metabolic phenotypes through a meta-analysis.

Methods: We performed a meta-analysis of studies with data on the association between rs641738C>T genotype and liver fat, NAFLD histology, and serum alanine aminotransferase (ALT), lipids or insulin. These included directly genotyped studies and population-level data from genome-wide association studies (GWAS). We performed a random effects meta-analysis using recessive, additive and dominant genetic models.

Results: Data from 1,066,175 participants (9,688 with liver biopsies) across 42 studies were included in the meta-analysis. rs641738C>T was associated with higher liver fat on CT/MRI (+0.03 standard deviations [95% CI 0.02-0.05], p = 4.8×10) and diagnosis of NAFLD (odds ratio [OR] 1.17 [95% CI 1.05-1.3], p = 0.003) in Caucasian adults. The variant was also positively associated with presence of advanced fibrosis (OR 1.22 [95% CI 1.03-1.45], p = 0.021) in Caucasian adults using a recessive model of inheritance (CC + CT vs. TT). Meta-analysis of data from previous GWAS found the variant to be associated with higher ALT (p = 0.002) and lower serum triglycerides (p = 1.5×10). rs641738C>T was not associated with fasting insulin and no effect was observed in children with NAFLD.

Conclusions: Our study validates rs641738C>T near MBOAT7 as a risk factor for the presence and severity of NAFLD in individuals of European descent.

Lay Summary: Fatty liver disease is a common condition where fat builds up in the liver, which can cause liver inflammation and scarring (including 'cirrhosis'). It is closely linked to obesity and diabetes, but some genes are also thought to be important. We did this study to see whether one specific change ('variant') in one gene ('MBOAT7') was linked to fatty liver disease. We took data from over 40 published studies and found that this variant near MBOAT7 is linked to more severe fatty liver disease. This means that drugs designed to work on MBOAT7 could be useful for treating fatty liver disease.
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http://dx.doi.org/10.1016/j.jhep.2020.08.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755037PMC
January 2021

Leptin, Resistin, and Proprotein Convertase Subtilisin/Kexin Type 9: The Role of STAT3.

Am J Pathol 2020 11 13;190(11):2226-2236. Epub 2020 Aug 13.

Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy. Electronic address:

In a condition of dysfunctional visceral fat depots, as in the case of obesity, alterations in adipokine levels may be detrimental for the cardiovascular system. The proinflammatory leptin and resistin adipokines have been described as possible links between obesity and atherosclerosis. The present study was aimed at evaluating whether proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of low-density lipoprotein metabolism, is induced by leptin and resistin through the involvement of the inflammatory pathway of STAT3. In HepG2 cells, leptin and resistin up-regulated PCSK9 gene and protein expression, as well as the phosphorylation of STAT3. Upon STAT3 silencing, leptin and resistin lost their ability to activate PCSK9. The knockdown of STAT3 did not affect the expression of leptin and resistin receptors or that of PCSK9. The analysis of the human PCSK9 promoter region showed that the two adipokines raised PCSK9 promoter activity via the involvement of a sterol regulatory element motif. In healthy males, a positive association between circulating leptin and PCSK9 levels was found only when the body mass index was <25 kg/m. In conclusion, this study identified STAT3 as one of the molecular regulators of leptin- and resistin-mediated transcriptional induction of PCSK9.
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http://dx.doi.org/10.1016/j.ajpath.2020.07.016DOI Listing
November 2020

Hepatic Fat-Genetic Risk Score Predicts Hepatocellular Carcinoma in Patients With Cirrhotic HCV Treated With DAAs.

Hepatology 2020 12 20;72(6):1912-1923. Epub 2020 Nov 20.

Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A. M. and A. Migliavacca" Center for Liver Disease, Milan, Italy.

Background And Aims: Genetic factors and steatosis predispose to hepatocellular carcinoma (HCC) in patients with chronic hepatitis C virus; however, their impact in patients with cirrhosis cured by direct-acting antivirals (DAAs) is still undefined. We assessed the association between a genetic risk score (GRS) of hepatic fat accumulation, combining variants in PNPLA3 (patatin-like phospholipase domain containing 3), MBOAT7 (membrane bound O-acyltransferase domain containing 7), TM6SF2 (transmembrane 6 superfamily member 2), GCKR (glucokinase regulator), and HCC in patients treated with DAAs.

Approach And Results: We considered 509 consecutive patients with HCV cirrhosis (defined histologically or when liver stiffness ≥12 kPa) treated with DAAs. HCC was diagnosed according to international recommendations. GRS was calculated from the weighted impact of single variants on hepatic fat content quantified by H spectrometry in the general population (Dallas Heart Study). During a median follow-up of 43 (3-57) months after DAA start, 36 of 452 (8%) patients developed de novo HCC, 4-year cumulative probability being 9% (95% confidence interval 7%-12%). Male sex (hazard ratio [HR] 2.54, P = 0.02), diabetes (HR 2.39, P = 0.01), albumin (HR 0.35, P = 0.001), and GRS score >0.597 (HR 2.30, P = 0.04) were independent predictors of de novo HCC. In contrast, single genetic risk variants were not useful in stratifying HCC risk. The proportion of patients who developed HCC according to the combination of the independent risk factors ranged from 11% to 67%. HCC recurred in 28 of 57 (49%) patients with previous history; diabetes and ethnicity were the only independent predictors of HCC recurrence.

Conclusions: In a large cohort of DAA-treated patients with cirrhotic HCV, GRS was associated with de novo HCC independently of classical risk factors, including liver disease severity. These data suggest that hepatic fat (i.e., lipotoxicity) promotes HCC in this setting and may represent a target for chemoprevention. Combination of clinical and genetic predictors may improve HCC risk stratification.
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http://dx.doi.org/10.1002/hep.31500DOI Listing
December 2020