La sfida della Cura della Salute nel Terzo Millennio

• Curare la Salute della Persona nella Sua Unicità e Complessità• Evolvere dalla cura impersonale e tardiva della lesione alla cura personalizzata della salute per

prevenire la lesione

La misura del grasso intra-epatico, uno specchio della

salute e corretto stile di vita personale

Prof. Ferruccio BoninoUPMC Institute for Health

Chianciano Terme Fondazione Italiana Fegato

The Grades of Quality of a Cure depends on Timeliness of Diagnosis and Care

PreventiveDiagnosis

EarlyDiagnosisand Care

RiparativeRe-habilitativeCare

Optimalto warrantcomplete recovery

May stillinduce

complete recovery

Complete recovery isnot possible any more

and the aim of care is to stop/limit the speedof disease progression

Asynptomatic Window

Cause/Etiology

PathogeneticProcess/Mechanism

Symptoms

The Level of Personalization/Quality of Medical Caredepends on the target

24.1%23.7%

31.8%

27.4%

13.5%

30.5%

Younossi et al. Hepatology, 2016

Worldwide prevalence of NAFLD

P

R

E

V

A

L

E

N

Z

A

Fegato Grasso – Studio DionysosPREVALENZA NELLA POPOLAZIONE GENERALE IN ITALIA: NAFLD = 25-30 % ; NASH = 2-3 %

Bellentani et al., Ann.Int.Med., 2000

NAFLD

NASH

Epatite

Rischio di Morte

age50 70 90

Malattie

Cardiovascolari

Metaboliche (Diabete)

Neoplastiche

Neurodegenerative

Malattie Suddette

Epatopatia

Epatopatia

Non alcoholic fatty liver disease (NAFLD) is a major independent risk factorassociated with overweight and inadequate life style

and the most sensitive biomarker in the asymptomatic subjectof the risk of death for cardiovascular diseases, type 2 diabetes

The prevalence of NAFLD in the general population is about 30 %, but it is 3 times higher in T2DM and 100% in obese patients with T2DM

The early identification of NASLD is mandatory to prevent thesediseases and their progression.

Among patho-physiologic mechanisms leading to NAFLD, common with T2DM are liver and muscle insulin resistance, however, it is mainly adipose tissue insulinresistance that results in increased hepatic de novo lipogenesis, inflammation, and lipotoxicity.

Although genetics predispose to NAFLD, an unhealthy lifestyle, includinghigh-fat/high-sugar diets and low physical activity, increases the risk. In addition, alterations in gut microbiota and environmental chemical agents, acting as endocrine disruptors play a role.

Saponaro C, Gaggini M, Gstaldelli A NAFLD and T2DM common pathophysiologic mechanims Curr Diab Rep. 2015;15(6):607

TG

GLP-1

Insulin

Lipolysis

FFA

Irisin

InflammationOxidative stress

AdiponectinLeptin

VLDL

VLDL

VLDL

VLDL

VLDL

Ghrelin

Acylated/deacylated

Ghrelin

Acylated/deacylated

Ghrelin

anti-inflammatory properties

WAT BAT Thermogenesis

FFA

DNL

β-oxidation FC

Lipogenesis

Glucose

Glucagon

Endothelial dysfunctionAtherosclerosis

GLP-1

GlycogenolysisGNG

SeP

Insulin Resistance

GNGGlycogenolysis

Inflammation

Glucotoxicity

VLDL

LDL

Hepatic IRSeP

Exercise / Insulin Resistance

Petta S, Gastaldelli A, Rebelos E, Bugianesi E, Messa P, Miele L, Svegliati-Baroni G, Valenti L, Bonino F. Pathophysiology of Non Alcoholic Fatty Liver Disease. Int J Mol Sci. 2016 Dec 11;17(12). pii: E2082.

Putative mechanisms linking NAFLD and extra-hepatic cancers

Mechanism Effects Extra-Hepatic Site Insulin resistance

↑ IGF-1 axis Proliferative and anti-apoptotic effects

Prostate/colorectal/lung/Breast cancers, Barrett’s esophagus, esophageal adenocarcinoma

Dysfunctional adipose tissue

↓ adiponectin/caspase activation ↓ adiponectin/TNF-α ↑ leptin/MAPK ↑ resistin/NF-κB

Anti-apoptotic effects Proliferation and angiogenesis Invasiveness, motility, lamellipodia formation

Gastrointestinal and extra-intestinal cancer Gastrointestinal and extra-intestinal cancer Colon/breast cancer, Barrett’s esophagus, esophageal adenocarcinoma Breast/gastrointestinal and non-small cell lung cancers

Inflammation IL-6/JAK/STAT3 and IL-6/MAPK TNF-α/Wnt/β-catenin

Proliferation Angiogenesis, differentiation and metastasis development

Renal/gastric/colorectal cancers Colorectal cancer

Gut microbiota MAMPs/TLRs Inflammasome-derived IL-18

Inflammation Anti-apoptotic effects

Colon cancer Colon cancer

IGF-1,insulingrowthfactor-1;IL,interleukin;MAMPs,microorganism-associated

molecularpatterns;MAPK,mitogen-activatedproteinkinase;NF-κB,nuclearfactor-κB;

STAT3,signaltransducerandactivatoroftranscription3;TLRs,toll-likereceptors;TNF-

α,tumornecrosisfactor-α.

Sanna C. et al. Int J Mol Sci. 2016 May; 17(5): 717

Libro Bianco dell’Associazione Italiana per lo Studio del Fegato-http://www.webaisf.org/media/13891/ libro-bianco-aisf-2011.pdf

Petta S, Valenti L, Bugianesi E, Targher G, Bellentani S, Bonino FSpecial Interest Group on Personalised Hepatology of the Italian Association for the Study of the Liver (AISF) A "systems medicine"approach to the study of non-alcoholicfatty liver disease. Dig Liver Dis. 2016 Mar;48(3):333-42.

European Association for the Study of the Liver (EASL), Association for the Studyof Diabetes (EASD), European Association for the Study of Obesity (EASO) ClinicalPractice Guidelines for the management of non-alcoholic fatty liver disease.J Hepatol. 2016 Jun;64(6):1388-402. doi: 10.1016/j.jhep.2015.11.004.

AISF POSITION PAPER ON NON ALCOHOLIC FATTY LIVER DISEASE (NAFLD): UPDATES AND FUTURE DIRECTIONS. Lonardo A, Nascimbeni F, Targher G,Bernardi M, Bonino F, Bugianesi E, Casini A, Gastaldelli A,Marchesini G, Marra F,Miele L, Morisco F, Petta S, Piscaglia F, Svegliati-Baroni GL, Valenti L, Bellentani S Dig Liver Dis. 2017 in press.

Is Liver Biopsy a Gold Standard? It is not.1/50.000

Steatosis Score: 65%

Steatosis Score: 15%

Steatosis is not

homogeneously

distributed in at least 30%

of cases;

Biopsy is invasive and

unsuitable

for tight monitoring

Magnetic Resonance Proton-Spectroscopy (1H-MRS) 1/150

Sonographic hepatic-renal ratio as indicator of hepatic steatosis: comparison with 1H

magnetic resonance spectroscopy

Metabolism Clinical and Experimental 58 (2009) 1724–1730

Castera L. et al Sem Liver Dis, 2015; Tapper EB, Afdahl NH. Curr Opin Gastroenterol , 2015

Liver Stiffness (LS)

7 8.7 10.3kPa

F0-F1 F2 F3 F4

Mild Sign Severe Cirrhosis

Matavir

Fibrosis

Congestion

Infiammation

Fibrosis

Bonino F et al Antivir Ther. 2010;

Castera L. Sem Liver Dis, 2015; Tapper EB and Afdahl NH. Curr OpinGastroenterol , 2015

Controlled Attenuation Parameter (CAP)

215 250 300 dB/m

S0 S1 S2 S3

<10%10-32% 33-66% >66%

Steatosis

% hepatocyteswith steatosis

86% 88% 87%Accuracy

measures the US attenuation rate by liver fat at 3.5 MHz frequ ency

Karlas T et al. Individual patient data meta-

analysis of controlled attenuation parameter

(CAP) technology for assessing steatosis.

J Hepatol. 2016 Dec 28. pii: S0168-

8278(16)30755-3. doi:

10.1016/j.jhep.2016.12.022.

The ultrasound based controlled attenuation

parameter (CAP) can be used to assess

steatosis, but factors such as the underlying

disease, BMI and diabetes must be taken into

accountUltrasound in Medicine & Biology 2010 61;36:1825-35

Figure 2

Imajo K et al Gastroenterology 2016 150, 626-637.e7DOI: (10.1053/j.gastro.2015.11.048)

Relationship between steatosis assessed by MRI-based PDFF and TE-based CAP

IngegneriFrancesco Faita (CNR – IFC)Nicole Di Lascio (SSSUP S. Anna)Nicola Martini (FTGM)

BiologiCinzia Avigo (CNR-IFC)

MediciMaurizia Rossana Brunetto (Università di Pisa, Epatologia AOUP)Filippo Oliveri, Barbara Coco, Antonio Salvati (Epato logia AOUP)Dante Chiappino (FTGM)Lorenzo Ghiadoni ( Università di Pisa, Medicina Urgenza AOUP)Rosa Maria Bruno (Medicina 1 AOUP)Ferruccio Bonino ( Università di Pisa, UPMC Institute for Health)

Steatometer: development of a software applicable to common US instruments for a reliable operator-indepen dentnon-invasive measure of liver fat

Progetto Ricerca Finalizzata 2013 CNR/SDN/Università di Pisa-Epatologia AOUP)

ECHOGRAPHIC FEATURESDRIVEN STEATOSIS QUANTIFICATION

Hepatic/renal ratio

Attenuation rate (CAP)

Hepatic/portal vein ratio

Diaphragm visualization

Portal vein wall visualization

First Order Statistics (Mean, STD, Skewness, Kurtosis Median, Mode)

Gray Level Co-occurrence Matrix (20 sub parameters)

Gray Level Run Length Matrix (48 sub parameters)

Gray Level Difference Matrix (4 sub parameters)

Laws Texture Energy (36 sub parameters)

Fractal Dimension

Wavelet Analysis (10 sub parameters)

Neighborhood Gray Tone Difference Matrix (5 sub parameters)

Clinical decision support system (CDSS)

CDSSSelected features(US + Biomarkers)

Steatosis score

Semi-autonomous diagnosis procedure

Selection of classifier: Bayesian with Gaussian model, k Nearest Neighbours,random forests and support vector machine

Learning phase

Liver RadarChart Status

Weighted linear combination:

US steato-grading =����1∙H/R ratio + ����2∙ attenuation rate +

����3∙ H/PV ratio – ����4∙diaphragm visualization -����5∙portal vein wall visualization

COMPARISON WITH MRS DATA

US-Steatometer

Best Accuracy, AUC, Sensitivity, Specificity and Youden index for > 5% liver fat content

Analysis of the inter/intra-operator/inter-session variabilities

Calculation of the Variability Coefficient for single parameters of the Steatometer Score obtained repeating the US analysis in 10 subjects at one hour time interval and changing operator

HR-ratio � VC = 4.75%HPV-ratio � VC = 7.22%AR � VC = 10.09%DV � VC = 10.8%HPV-wall � 4.96%Overall Steatometer Index � VC=7.50%

E’ necessario quindi un approccio di Medicina Sistematica per la Prototipizzazione dei Soggetti a Rischio e una

Adeguata Personalizzazione della Cura

Lee Kaplan, M.D., director of the Obesity, Metabolism, and Nutrition Instituteat Massachusetts General Hospital, tells the Times that there are at least59 types of obese subjects

1 2 3

6 clusters of obese individuals:

young healthy femalesfewer obesity-related complications(ie. Type 2 D)

heavy-drinking maleshigher alcohol intake

unhappy and anxious middle-agedpredominantly women with poormental health

wellbeing affluent and healthy elderlygenerally positive health, but higheralcohol intake and high blood pressure

physically sick but happy elderlyolder people with more chronic diseases, but good mental health

poorest healththe most economically deprived with the greatest number of chronic diseases

Critical events to gain weight

Females: Pregnancy / Post-Menopause

Males: Beginning of Working Life

Preventiva Precoce Tardiva

Timing/Efficacia della Cura

1 2 3O

Target of Bariatric Surgery and

Non-reversible GI Modifications

Targets of ReversibleGI Modifications

Major Negative Prognostic Factorsto be taken into account

for personal care

Hypoventilation SyndromeOSAS

Inflammation (NASH) Gut Microbiota Rehabilitation

Mirrakimov AE and Polotsky VY. Obstructive Sleep Apnea and Non-Alcoholic Fatty Liver Disease: Is the Liver Another Target?Front Neurol. 2012; 3: 149.

Switch of non invasive ventilation (NIV) to continu ous positive airway pressure (CPAP) in patients with obesity hyp oventilation syndrome: a pilot studyOrfanos S et al BMC Pulm Med. 2017; 17: 50.

NIV CPAP

Mandibular Advancement Device

Lin and Zhang BMC Immunology (2017) 18:2

ANALISI METAGENOMICA DEL DNA FECALE PER 15 CEPPI PRINCIPALI

ENTEROCOCCUS (COD. 91.30.1), E. COLI (COD. 91.30.1), BIFIDOBACTERIUM (COD. 91.30.1), STREPTOCOCCUS (COD. 91.30.1), CANDIDA ALBICANS (COD. 91.30.1), ENTEROBACTERIACEAE (COD. 91.30.1), FIRMICUTES (COD. 91.30.1), BACTEROIDETES (COD. 91.30.1), BACTEROIDES (COD. 91.30.1), PREVOTELLA (COD. 91.30.1), LACTOBACILLUS (COD. 91.30.1), LACTOBACILLUS ACIDOPHILUS (COD. 91.30.1), CLOSTRIDIUM PERFRINGENS (COD. 91.30.1), HELICOBACTER PYLORI (COD. 91.30.1), STAPYLOCOCCUS AUREUS (COD. 91.30.1)

Chronic PPItreatment

La prevenzione abbinata all’appropriata personalizzazione prescrittiva rappresenta la più efficace spending review sanitaria

• Spesa farmaceutica Annuale totale circa 28 miliardi di euro, di cui il 75% rimborsato dal SSN

• I PPI sono circa l’11% della spesa = 3,0 miliardi euro di cui 80% inappropriati, quindi

• Con 2,4 miliardi risparmiati si eradica l’infezione da HCV e si copre la spesa per i farmaci oncologici innovativi

Survival curves for PPI and H2 blockers.

Yan Xie et al. BMJ Open 2017;7:e015735

©2017 by British Medical Journal Publishing Group

Duration of PPI exposure and risk of death among ne w PPI users (n=166  098).

Yan Xie et al. BMJ Open 2017;7:e015735

©2017 by British Medical Journal Publishing Group

Personalized HealthAssessment & Care

AgeGeneticsLiver

FatContent

100%

50%

0%0%Exercise

Life Style

FoodOtherRisk

Factors

The Impact of Genetics

• PNPLA3 patatin like phospholipase domain containing 3 http://www.ncbi.nlm.nih.gov/gene/80339

• TM6SF2 transmembrane 6 superfamilymember 2

• http://www.ncbi.nlm.nih.gov/gene/53345

InternistaEndocrinologo, Epatologo,..

Dietologo/Nutrizionista

Psicologo/PsichiatraFisioterapistaTrainer Sportivo

Specialista OperativoEndoscopista, Chirurgo

MMG/Supervisore

Briefings Periodici

Team Work Obbligatorio

Il percorso del paziente è riferibile a quello dell’ auto condotta dal guidatore per un determinato segmento di percorso (diagnostico-terapeutico). Il guidatore è accompagnato da 3-4 colleghi che lo consigliano sul percorso e che a loro volta si alternano alla guida.

Il paziente-autoè direttamentepartecipe, attore e autore del percorso di cura

Cars – Disney-Pixar

Casati S, Monti P, Bonino F From actors to authors: a first account about the involvement of patients In the informed consent governance of a major italian translational research hospitalJ Ambul Care Management. 2010 Jul-Sep;33(3):231-40.

Normale Grasso

La misura del grasso intra -epatico manometro dell’efficacia della cura nel singolo pazi ente

ColesteroloHDL

ALT/ASTGGT

Glicemia Insulina

Fine II – Inizio I Secolo A.C. Il fegato indice di salute generale

per l’ aruspice

Fine XX – Inizio XXI Secolo D.C.Il nostro fegato specchio

di salute individuale

Ritorno al Futuro: il fegato specchio di salute nella storia come nella pratica clinica

Il Fegato Specchio della Salute

Hepatology UnitUniversity Hospital of Pisa, Italy

Director Prof. Maurizia Rossana Brunetto

Medical Doctors

Barbara CocoPiero ColombattoFilippo OliveriVeronica RomagnoliAntonio SalvatiGabriele RiccoRiccardo GattaiLidia Surace

Nurses

Antonella CristofaniSimonetta Ferretti (part-time)Simona GiannettiTeresa Crisponi Barbara ZucchelliElena Centi

Arianna Del Chicca

Biologists

Daniela CavalloneFrancesco MoriconiPierpaola Tannorella

Bio-Physics – EngineersLuigi CivitanoFrancesco FaitaRanieri Bizzarri

Administrative Personel

Seo SW, Gottesman RF, Clark JM, Hernaez R, Chang Y, Kim C, Ha KH, Guallar E, Lazo M

Non alcoholic fatty liver disease is associated with cognitive function in adults

Reduced brain activity in female patients with non alco holic fatty liver diseaseas measured by near infrared spectroscopy

Takahashi A et Al. 2017

European Association for the Study of the Liver (EASL), Association for the Studyof Diabetes (EASD), European Association for the Study of Obesity (EASO) ClinicalPractice Guidelines for the management of non-alcoholic fatty liver disease .J Hepatol. 2016 Jun;64(6):1388-402. doi: 10.1016/j.jhep.2015.11.004.

Petta S, Valenti L, Bugianesi E, Targher G, Bellentani S, Bonino FSpecial Interest Group on Personalised Hepatology of AISF A "systems medicine"approach to the study of non-alcoholicfatty liver disease. Dig Liver Dis. 2016 Mar;48(3):333-42.

AISF POSITION PAPER ON NONALCOHOLIC FATTY LIVER DISEASE (NAFLD): UPDATES AND FUTURE DIRECTIONS. Lonardo A, Nascimbeni F, Targher G,Bernardi M, Bonino F, Bugianesi E, Casini A, Gastaldelli A,Marchesini G, Marra F,Miele L, Morisco F, Petta S, Piscaglia F, Svegliati-Baroni GL, Valenti L, Bellentani S Dig Liver Dis. 2017 in press.