Effetti di diverse tecniche di Chirurgia Bariatrica sull\u2019Omeostasi Metabolica in pazienti Obesi

La chirurgia bariatrica si \ue8 dimostrata efficace nel determinare la remissione del diabete tipo 2 nei soggetti obesi, tuttavia il meccanismo con cui le diverse tecniche chirurgiche agiscono sulla secrezione \u3b2-cellulare e sulla modulazione dell\u2019insulino-resistenza non \ue8 ancora completamente chiarito. Scopo: valutare in modo prospettico gli effetti di diverse tecniche di chirurgia bariatrica (bendaggio gastrico, sleeve gastrectomy, bypass gastrico) sul calo ponderale e sul compenso glicometabolico in pazienti obesi diabetici, e individuare, in un sottogruppo di questi pazienti, i meccanismi attraverso cui l\u2019intervento di chirurgia bariatrica modifica l\u2019omeostasi del glucosio. Metodi: Sono stati arruolati 104 obesi diabetici, (66 F; 38 M) sottoposti consecutivamente a chirurgia bariatrica; 11 pazienti sono stati sottopostia a Bendaggio Gastrico Regolabile (LAGB) (et\ue0 47,3\ub12,9 anni; BMI 42,3\ub12,5 kg/m2), 77 a Bypass Gastrico (RYGB) (et\ue0 49.0\ub1 0,1 anni; BMI 45,7\ub10,76 kg/m2) e 16 a Sleeve gastrectomy (SG) (et\ue0 50,0\ub12,3 anni; BMI 50,7\ub12,2 kg/m2). I pazienti erano eterogenei per durata di malattia e per trattamento antidiabetico. 5 soggetti (2M; 3F), et\ue0 media 48,2\ub14,3 anni, peso 112,5\ub17,9 kg, BMI 40,9\ub12,7 kg/m2, durata di diabete: 5,6 anni (range 3-12 aa), HbA1c 7,6\ub1 0,6%, sono stati sottoposti a test pasto-misto (186 Kcal: 53% carboidrati, 17% proteine, 30% grassi) prima e 1 mese dopo chirurgia (RYBP), con dosaggio di glicemia, C-peptide, insulina, lattato, e GIP per 5 ore. La funzione \u3b2-cellulare \ue8 stata valutata mediante analisi modellistica delle curve glucosio/C-peptide durante pasto e costruzione della curva stimolo (glicemia)-risposta (secrezione di insulina). La valutazione di massa grassa e massa magra negli arti e nel tronco, prima e 1 mese dopo chirurgia, \ue8 stata eseguita mediante DEXA. Risultati: I 104 pazienti hanno presentato un calo ponderale medio a 12 mesi del 26,5\ub11,46 % che si \ue8 mantenuto a 24 e 36 mesi. La remissione del diabete a 36 mesi \ue8 stata evidenziata nel 56,5% dei pazienti (nel 50,0% dei pazienti sottoposti a LAGB, 56% dei pazienti sottoposti a RYGB, e 100% dei pazienti sottoposti a SG). La durata di malattia \ue8 risultato l\u2019unico predittore della persistenza del diabete a 24 e 36 mesi. Nei 5 pazienti sottoposti a test con pasto misto (secondo protocollo pubblicato su ClinicalTrials.gov NCT 01767441), dopo un mese dall\u2019intervento \ue8 stato evidenziato un significativo calo ponderale: \u394massa-totale -10,62\ub10,61 kg p<0,001, \u394BMI -4,07\ub10,26 kg/m2 p<0,001, \u394grasso-tot -5,58\ub10,74 kg p<0,007; \u394grasso del torso (-4,13\ub10,69 p<0,04). Dopo un mese dall\u2019intervento, glicemia e insulina a digiuno calavano (glicemia 9,6\ub11,18 vs 5,5\ub10,47 mmol/L, p=ns; insulina 231,36\ub121,17 vs 64,92\ub14,41 pmol/L, p=0,02), come anche HOMA-IR (17,2\ub14,8 vs 2,7\ub10,61 p=0,04). Si riduceva inoltre l\u2019area sotto la curva insulinemica (66,43\ub110.5 vs 28.67\ub17.4 nmol/l in 4 ore; p=0,039) e l\u2019area sotto la curva del lattato (256,03\ub134,76 vs 183,77\ub132,89 mmol/l in 4 ore; p=0,02) mentre la risposta del GIP al pasto misto ha mostrato una tendenza all\u2019aumento (AUC 19,14\ub15,14 vs 23,72\ub13,4 ng/ml in 4 ore, p=ns). Infine, la funzione \u3b2-cellulare migliorava significativamente (p<0.04) come dimostrato dallo spostamento a sinistra della curva stimolo-risposta. Conclusioni: Nella maggior parte dei nostri pazienti, il calo ponderale dopo chirurgia bariatrica si mantiene fino a 3 anni di follow-up e la remissione completa del diabete a 3 anni riguarda oltre il 50 % dei diabetici, senza evidenza di recidive. I dati preliminari del test pasto misto, dopo 30 giorni dall\u2019intervento di RYBP, suggeriscono che il miglioramento dell\u2019omeostasi glucidica sia attribuibile a concomitanti incrementi della funzione \u3b2-cellulare e della sensibilit\ue0 insulinica, con contemporanea riduzione della glicolisi anaerobia. Tali miglioramenti sono ottenuti in presenza di una significativa riduzione dell\u2019impegno biochimico della \u3b2-cellula.Bariatric surgery can lead to improvement or even resolution of type 2 diabetes Mellitus (T2DM) with the spectrum of responses depending also on operation procedures. However, many underlying mechanisms of metabolic action of different surgical techniques are still unclear. The aim of this study was evaluate the long-term effects of bariatric surgery on weight loss and T2DM remission and to provide a better understanding of the effects of surgery on \u3b2-cell function and incretin secretion. METHODS: The study included 104 obese T2DM patients (66 women and 38 men, ) who were wait-listed for laparoscopic gastric banding (LAGB, 11 subjects, age 47,3\ub12,9 y, BMI 42,3\ub12,5 kg/m2), or for laparoscopic Roux-en-Y gastric bypass (RYBP , 77 subjects, age 49,7\ub10,1 y, BMI 45,7\ub10,7 kg/m2), or for sleeve gastrectomy (SG, 16 subjects, age 50,9\ub12,3 y, BMI 50,7\ub12,2 kg/m2) In 5 patients a mixed meal tolerance test (MMT: 186 Kcal; 53% carbohydrate, 30% fat, 17% protein) was performed before and 1 and 12 months after RYBP to assess hormonal changes. During MMT blood samples were collected for 300 minutes for the measurement of plasma glucose, insulin, C-peptide, lactate and GIP. \u3b2-cell function parameters were derived from mathematical modelling of plasma glucose, insulin and C-peptide concentrations. Body composition, fat mass and fat-free mass were evaluated before and 1 and 12 months after RYBP by means of DEXA. RESULTS: The average percentage of weight loss after surgery in the 104 patients was 26,5\ub11,46% and it was maintained at 24 and 36 months follow-up. Diabetes remission at 3 years follow-up occurred in 56,5% of study participants (in 50,0% of LAGB, 56% of RYBP and 100% of SG). Duration of diabetes was the only significant predictor of diabetes remission at 2 and 3 years. The 5 patients who underwent MMT (according to ClinicalTrials.gov protocol NCT 01767441), showed, 1 month after RYBP, a significant weight loss: \u394BMI=- 4,07\ub10,26 kg/m2 p<0,001, \u394total mass= -10,62\ub10,61 kg, \u394total-fat= -5,58\ub10,74 kg p<0,007. HOMA-IR and plasma insulin decreased (HOMA-IR 17,2\ub14,8 vs 2.7\ub10.61 p=0,04; plasma insulin 231,36\ub121,17 vs 64,92\ub14,41 pmol/L, p=0,02) as well as insulin AUC and lactate AUC (respectively 66,43\ub110,5 vs 28,67\ub15,51 nmol/l in 4 hour; p=0,039 and 258,03\ub134,76 vs 183,77\ub132,89 mmol/l in 4 hour; p=0,02). Insulin secretion rate significantly improved (p<0,04). CONCLUSIONS Bariatric Surgery appears to be a viable option for the treatment of severe obesity, resulting in long term weight loss and frequent diabetes remission. Our preliminary data suggest that amelioration in glucose homeostasis, evaluated by a physiological stimulus (MMT), could be related to improvement in \u3b2-cell function and insulin sensitivity

STEATOEPATITE NON ALCOLICA E FIBROSI EPATICA IN UNA CASISTICA DI PAZIENTI OBESI SOTTOPOSTI A CHIRURGIA BARIATRICA

Obiettivi dello studio: Valutare la prevalenza di epatopatia steatosica non alcolica (NAFLD) ed in particolare di steatoepatite non alcolica (NASH) e fibrosi epatica in pazienti con obesit\ue0 grave, che sono candidati ad intervento di chirurgia bariatrica. E\u2019 stato inoltre valutato l\u2019andamento delle transaminasi plasmatiche, adiponectina e di alcuni scores non invasivi di fibrosi epatica avanzata dopo 6 e 12 mesi dall\u2019intervento chirurgico.Popolazione e Metodi: Abbiamo studiato un campione di 28 pazienti affetti da obesit\ue0 grave (75% donne, et\ue0 mediana 41 anni, BMI mediano 45 kg/m\ub2), che sono stati sottoposti ad intervento in elezione di sleeve gastrectomy (19 pazienti) o bypass gastrico (9 pazienti). In tutti i pazienti sono stati eseguiti accertamenti metabolici (incluso 2-h clamp euglicemico iperinsulinemico) al baseline ed \ue8 stata eseguita una biopsia epatica durante l\u2019intervento chirurgico. Nessuno di questi pazienti aveva un eccessivo consumo di alcoolici n\ue9 una precedente storia di cirrosi e/o altre epatopatie croniche note.Risultati: Dei 28 pazienti inclusi nello studio, 16 (57%) hanno soddisfatto i criteri istologici per una diagnosi di NASH, mentre i restanti 12 (43%) pazienti non avevano NASH al baseline. Di questi 12 pazienti privi di NASH alla biopsia, 8 pazienti avevano steatosi macrovescicolare di grado lieve o severo (NAFL), mentre solo 4 pazienti (pari al 14.3% del campione totale) erano esenti da NAFLD alla biopsia epatica. Per quanto riguarda il grado di fibrosi epatica, 4 pazienti (14.3%) non avevano fibrosi (stadio F0), 14 (50%) pazienti avevano fibrosi moderata (F2) e 10 (35.7%) avevano \u201cbridging fibrosis\u201d (F3). Nessuno dei pazienti aveva cirrosi epatica precedentemente misconosciuta (F4). Quando i pazienti venivano suddivisi sulla base della presenza/assenza di NASH e/o della severit\ue0 di fibrosi epatica (F3 vs. F0-2), i due gruppi di pazienti erano comparabili per et\ue0, sesso e le principali variabili biochimiche esaminate, incluso transaminasi, APRI index, FIB-4 score e sensibilit\ue0 insulinica (M-clamp). L\u2019intervento chirurgico induceva, sia dopo 6 che 12 mesi, un marcato calo ponderale ed una significativa riduzione dei livelli circolanti di adiponectina in entrambi i gruppi. Al contrario, i valori di transaminasi e gli scores non invasivi di fibrosi epatica avanzata non hanno mostrato alcuna significativa variazione dopo 6 e 12 mesi dall\u2019intervento chirurgico in nessuno dei gruppi di pazienti considerati (NASH vs. no-NASH e F3 vs. F0-2).Conclusioni: Nei nostri pazienti con obesit\ue0 grave, candidati a chururgia bariatrica, la NAFLD \ue8 una patologia assai comune (essendo presente in circa 85% del campione) ed \ue8 gi\ue0 presente anche nelle sue forme istologiche pi\uf9 severe (NASH nel 57% dei casi e fibrosi avanzata nel 35.7% dei casi), pur rimanendo queste forme spesso clinicamente silenti (o pauci-sintomatiche) e senza accompagnarsi a significative alterazioni delle transaminasi circolanti e degli scores non-invasivi di fibrosi avanzata. Questi dati suggeriscono la necessit\ue0 di una diagnosi precoce e tempestiva delle forme pi\uf9 severe della NAFLD (che sono quelle associate ad un maggior rischio di progressione verso la cirrosi e l\u2019epatocarcinoma) in tutti i soggetti obesi che vengono sottoposti a chirurgia bariatrica (da eseguirsi almeno in fase intra-operatoria)

Refinement of the diagnostic approach for the identification of children and adolescents affected by familial hypercholesterolemia: Evidence from the LIPIGEN study

Background and aims: We aimed to describe the limitations of familiar hypercholesterolemia (FH) diagnosis in childhood based on the presence of the typical features of FH, such as physical sings of cholesterol accumulation and personal or family history of premature cardiovascular disease or hypercholesterolemia, comparing their prevalence in the adult and paediatric FH population, and to illustrate how additional information can lead to a more effective diagnosis of FH at a younger age.Methods: From the Italian LIPIGEN cohort, we selected 1188 (&gt;= 18 years) and 708 (&lt;18 years) genetically-confirmed heterozygous FH, with no missing personal FH features. The prevalence of personal and familial FH features was compared between the two groups. For a sub-group of the paediatric cohort (N = 374), data about premature coronary heart disease (CHD) in second-degree family members were also included in the evaluation.Results: The lower prevalence of typical FH features in children/adolescents vs adults was confirmed: the prevalence of tendon xanthoma was 2.1% vs 13.1%, and arcus cornealis was present in 1.6% vs 11.2% of the cohorts, respectively. No children presented clinical history of premature CHD or cerebral/peripheral vascular disease compared to 8.8% and 5.6% of adults, respectively. The prevalence of premature CHD in first-degree relatives was significantly higher in adults compared to children/adolescents (38.9% vs 19.7%). In the sub-cohort analysis, a premature CHD event in parents was reported in 63 out of 374 subjects (16.8%), but the percentage increased to 54.0% extending the evaluation also to second-degree relatives.Conclusions: In children, the typical FH features are clearly less informative than in adults. A more thorough data collection, adding information about second-degree relatives, could improve the diagnosis of FH at younger age

Twelve Variants Polygenic Score for Low-Density Lipoprotein Cholesterol Distribution in a Large Cohort of Patients With Clinically Diagnosed Familial Hypercholesterolemia With or Without Causative Mutations

: Background A significant proportion of individuals clinically diagnosed with familial hypercholesterolemia (FH), but without any disease-causing mutation, are likely to have polygenic hypercholesterolemia. We evaluated the distribution of a polygenic risk score, consisting of 12 low-density lipoprotein cholesterol (LDL-C)-raising variants (polygenic LDL-C risk score), in subjects with a clinical diagnosis of FH. Methods and Results Within the Lipid Transport Disorders Italian Genetic Network (LIPIGEN) study, 875 patients who were FH-mutation positive (women, 54.75%; mean age, 42.47±15.00 years) and 644 patients who were FH-mutation negative (women, 54.21%; mean age, 49.73±13.54 years) were evaluated. Patients who were FH-mutation negative had lower mean levels of pretreatment LDL-C than patients who were FH-mutation positive (217.14±55.49 versus 270.52±68.59 mg/dL, P<0.0001). The mean value (±SD) of the polygenic LDL-C risk score was 1.00 (±0.18) in patients who were FH-mutation negative and 0.94 (±0.20) in patients who were FH-mutation positive (P<0.0001). In the receiver operating characteristic analysis, the area under the curve for recognizing subjects characterized by polygenic hypercholesterolemia was 0.59 (95% CI, 0.56-0.62), with sensitivity and specificity being 78% and 36%, respectively, at 0.905 as a cutoff value. Higher mean polygenic LDL-C risk score levels were observed among patients who were FH-mutation negative having pretreatment LDL-C levels in the range of 150 to 350 mg/dL (150-249 mg/dL: 1.01 versus 0.91, P<0.0001; 250-349 mg/dL: 1.02 versus 0.95, P=0.0001). A positive correlation between polygenic LDL-C risk score and pretreatment LDL-C levels was observed among patients with FH independently of the presence of causative mutations. Conclusions This analysis confirms the role of polymorphisms in modulating LDL-C levels, even in patients with genetically confirmed FH. More data are needed to support the use of the polygenic score in routine clinical practice

Lipoprotein(a) Genotype Influences the Clinical Diagnosis of Familial Hypercholesterolemia

: Background Evidence suggests that LPA risk genotypes are a possible contributor to the clinical diagnosis of familial hypercholesterolemia (FH). This study aimed at determining the prevalence of LPA risk variants in adult individuals with FH enrolled in the Italian LIPIGEN (Lipid Transport Disorders Italian Genetic Network) study, with (FH/M+) or without (FH/M-) a causative genetic variant. Methods and Results An lp(a) [lipoprotein(a)] genetic score was calculated by summing the number risk-increasing alleles inherited at rs3798220 and rs10455872 variants. Overall, in the 4.6% of 1695 patients with clinically diagnosed FH, the phenotype was not explained by a monogenic or polygenic cause but by genotype associated with high lp(a) levels. Among 765 subjects with FH/M- and 930 subjects with FH/M+, 133 (17.4%) and 95 (10.2%) were characterized by 1 copy of either rs10455872 or rs3798220 or 2 copies of either rs10455872 or rs3798220 (lp(a) score ≥1). Subjects with FH/M- also had lower mean levels of pretreatment low-density lipoprotein cholesterol than individuals with FH/M+ (t test for difference in means between FH/M- and FH/M+ groups &lt;0.0001); however, subjects with FH/M- and lp(a) score ≥1 had higher mean (SD) pretreatment low-density lipoprotein cholesterol levels (223.47 [50.40] mg/dL) compared with subjects with FH/M- and lp(a) score=0 (219.38 [54.54] mg/dL for), although not statistically significant. The adjustment of low-density lipoprotein cholesterol levels based on lp(a) concentration reduced from 68% to 42% the proportion of subjects with low-density lipoprotein cholesterol level ≥190 mg/dL (or from 68% to 50%, considering a more conservative formula). Conclusions Our study supports the importance of measuring lp(a) to perform the diagnosis of FH appropriately and to exclude that the observed phenotype is driven by elevated levels of lp(a) before performing the genetic test for FH

Spectrum of mutations in Italian patients with familial hypercholesterolemia: New results from the LIPIGEN study

Background Familial hypercholesterolemia (FH) is an autosomal dominant disease characterized by elevated plasma levels of LDL-cholesterol that confers an increased risk of premature atherosclerotic cardiovascular disease. Early identification and treatment of FH patients can improve prognosis and reduce the burden of cardiovascular mortality. Aim of this study was to perform the mutational analysis of FH patients identified through a collaboration of 20 Lipid Clinics in Italy (LIPIGEN Study). Methods We recruited 1592 individuals with a clinical diagnosis of definite or probable FH according to the Dutch Lipid Clinic Network criteria. We performed a parallel sequencing of the major candidate genes for monogenic hypercholesterolemia (LDLR, APOB, PCSK9, APOE, LDLRAP1, STAP1). Results A total of 213 variants were detected in 1076 subjects. About 90% of them had a pathogenic or likely pathogenic variants. More than 94% of patients carried pathogenic variants in LDLR gene, 27 of which were novel. Pathogenic variants in APOB and PCSK9 were exceedingly rare. We found 4 true homozygotes and 5 putative compound heterozygotes for pathogenic variants in LDLR gene, as well as 5 double heterozygotes for LDLR/APOB pathogenic variants. Two patients were homozygous for pathogenic variants in LDLRAP1 gene resulting in autosomal recessive hypercholesterolemia. One patient was found to be heterozygous for the ApoE variant p.(Leu167del), known to confer an FH phenotype. Conclusions This study shows the molecular characteristics of the FH patients identified in Italy over the last two years. Full phenotypic characterization of these patients and cascade screening of family members is now in progress

The Role of Registers in Increasing Knowledge and Improving Management of Children and Adolescents Affected by Familial Hypercholesterolemia: the LIPIGEN Pediatric Group

Pathology registers can be a useful tool to overcome obstacles in the identification and management of familial hypercholesterolemia since childhood. In 2018, the LIPIGEN pediatric group was constituted within the Italian LIPIGEN study to focus on FH subjects under 18 years. This work aimed at discussing its recent progress and early outcomes. Demographic, biochemical, and genetic baseline characteristics were collected, with an in-depth analysis of the genetic defects. The analysis was carried out on 1,602 children and adolescents (mean age at baseline 9.9 ± 4.0 years), and almost the whole cohort underwent the genetic test (93.3%). Overall, the untreated mean value of LDL-C was 220.0 ± 97.2 mg/dl, with an increasing gradient from subjects with a negative (N = 317; mean untreated LDL-C = 159.9 ± 47.7 mg/dl), inconclusive (N = 125; mean untreated LDL-C = 166.4 ± 56.5 mg/dl), or positive (N = 1,053; mean untreated LDL-C = 246.5 ± 102.1 mg/dl) genetic diagnosis of FH. In the latter group, the LDL-C values presented a great variability based on the number and the biological impact of involved causative variants. The LIPIGEN pediatric group represents one of the largest cohorts of children with FH, allowing the deepening of the characterization of their baseline and genetic features, providing the basis for further longitudinal investigations for complete details

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life

Familial hypercholesterolemia: The Italian Atherosclerosis Society Network (LIPIGEN)

BACKGROUND AND AIMS: Primary dyslipidemias are a heterogeneous group of disorders characterized by abnormal levels of circulating lipoproteins. Among them, familial hypercholesterolemia is the most common lipid disorder that predisposes for premature cardiovascular disease. We set up an Italian nationwide network aimed at facilitating the clinical and genetic diagnosis of genetic dyslipidemias named LIPIGEN (LIpid TransPort Disorders Italian GEnetic Network). METHODS: Observational, multicenter, retrospective and prospective study involving about 40 Italian clinical centers. Genetic testing of the appropriate candidate genes at one of six molecular diagnostic laboratories serving as nationwide DNA diagnostic centers. RESULTS AND CONCLUSIONS: From 2012 to October 2016, available biochemical and clinical information of 3480 subjects with familial hypercholesterolemia identified according to the Dutch Lipid Clinic Network (DLCN) score were included in the database and genetic analysis was performed in 97.8% of subjects, with a mutation detection rate of 92.0% in patients with DLCN score 656. The establishment of the LIPIGEN network will have important effects on clinical management and it will improve the overall identification and treatment of primary dyslipidemias in Italy

Effects of selective H.E.L.P. LDL-apheresis on plasma inflammatory markers concentration in severe dyslipidemia: Implication for anti-inflammatory response.

Therapeutic plasmapheresis is a recognized medical procedure in which various techniques are used to separate and remove undesirable or excessively elevated plasma elements from blood. The main purpose of the procedure is to remove the substances responsible for the disease (autoantibodies, circulating immune complexes, lipoproteins and other molecules) from the patient’s blood. Low-Density-Lipoproteins- apheresis (LDL_a) is the selective removal of all apolipoprotein-B100-containing lipoproteins: LDL, very low-density lipoprotein, and lipoprotein (a). They are lowered acutely by 65–75%. There is little effect on other plasma lipidic and non-lipidic components. LDL_a was reported to increase resistance of LDL to oxidation, counteract procoagulatory state and relief disturbances of hemorheology associated with atherosclerosis. These effects are likely to be regarded as to be pleiotropic effects. In the sense that they are not necessarily related to the apolipoprotein-B100-containing lipoproteins level in plasma. There is robust evidence that LDL_a can induce the stabilization of atherosclerotic plaques through its lipidlowering action. However, other effects unrelated to the apolipoprotein-B100-containing lipoproteins extracorporeal removal, such as the decrease of cytokines and adhesion molecules induced by LDL_a were also reported. Altogether these actions are thought to favorably influence regression of florid, nonfibrous atherosclerotic lesions through a blockade of lipid deposition in the vessel wall, plaque stabilization, and ultimately, coronary and extracoronary artery disease progression. This brief review provides some indication on existing evidence of Heparin-induced Extracorporeal Low-density-lipoprotein Precipitation LDL_a effects on plasma mediators of inflammation