EPIDEMIOLOGIA DELLE EPATOPATIE CRONICHE IN ITALIA: IL PESO DELLA NAFLD

Stefano Bellentani, M.D., Ph.D.Fondazione Italiana Fegato (FIF), Bassovizza (Trieste)

e Gastroenterologia , RIPED, NOCSE, Modenae.mail: bellentanistefano@gmail.com

Il sottoscritto dichiara di aver avuto negli ultimi 12 mesi conflitto d’interesse in relazione a questa presentazione : ROTTAPHARM-MEDA

Prof. Paola Loria (18 luglio 1951 - 7 luglio 2014)

CHRONIC LIVER DISEASES ETIOLOGIES: PAST, PRESENT AND FUTURE

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Forms and aetiology of NAFLD

“Primary” NAFLD: Associated with the metabolic syndrome

“Secondary” NAFLD: Associated with different conditions

Drugs: Steroids, Amiodarone, Tamoxifen, anti-HIV drugs, etc.

Metabolic or genetic alterations: Lipodystrophy, Dysbetalipoproteinemia, Weber-Christian disease

Nutritional: TPN, Rapid weight loss, Bariatric surgery, Starvation

Small bowel diseases: IBD, Bacterial overgrowth

Environmental hepatotoxins: e.g. Petrochemicals

Steatosis accompanying other forms of liver disease

Fatty Liver at USor alteration of LE

Exlude HBV and HCV infection and other causes of liver diseases

Evaluate with accuracy alcohol intake

Alcohol intake 20 g/day

Alcohol intake > 20 g/day

NAFLD AFLD

Insulin resistence(Metabolic Syndrome)

FATTY LIVER

AlcoholicAFLD

Non-alcoholicNAFLD

Steatosis80-90%

NASH 10-20%

NAFLDobesity, type 2 DM, dyslipidemia, metabolicsyndromeAFLDAlcohol abuse

ASH 20-30%

Components of the Metabolic Syndrome

Cormons

Campogalliano

Screening della popolazione generale(range età 12-65 anni);

Città comparabili in termini di redditopro-capite e caratteristiche demografich

6841 soggetti esaminati nel 1992 e6781 nel 2002 (68% e 60% dei soggettiarruolati);

Valutazione introito alcolico ed alimenticon diario dei 7 giorni e questionariosemiquantitativo illustrato;

AST, ALT, GGT, MCV, piastrine,HBsAg, Anti-HCV;

Anamnesi farmacologico e storia di epatopatie;

Esame obiettivo, BMI;

Progetto Dionysos(1992-2002)

*Risk threshold for developing liver disease (> 30 gr/day x both sexes)

ConditionPrevalence

Liver disease Prevalence

Amongexposed

General Population

HCV 3,2%(221/6917)

50%(110/221)

1,6%(110/6917) 

HBV 1,2%(83/6917)

25%(21/83)

0,3%(21/6917)

Alcohol* 21%(1349/6917)

5,5%(74/1349) 

1,1%(74/6917) 

NAFLD 25%(1729/6917)

7,9‐11,9%(138‐207/1729)

estimated

2‐3% (138‐207/6917)

estimated

Italy: The Dionysos Study

Bellentani S et al, Dig Dis 2010Bedogni G et al, Hepatology 2005Bellentani S et al, Gut 1999Bellentani S et al, Gut 1997Bellentani S et al, Hepatology 1994

PREVALENZA DELLE EPATOPATIE IN POPOLAZIONE GENERALE

“NASH è oggi la terzaindicazione al trapiantoepatico in USA ed è in incremento costante tantoda diventare tra breve la cuasa piu’ comune.”

Eziologia dell’epatopatia PrevalenzaNAFLD Fino al 33%HCV 2%Epatopatia alcolica 1%HBV 0,3-0,4%Emocromatosi da mutazioni del gene HFE 1:200-1:400Epatopatie autoimmuni Fino a 17/100.000Deficit di α1-antitripsina 1/1500-1/7600Malattia di Wilson 1/30.000

Charlton MR, Gastroenterology. 2011;141:1249-53.

Loria P, Dig Liver Dis. 2010;42:272-82.

0%

24%

15%18%

17%

19% 20%24%

31%32%10%

8%

22%25%26%

32%30% 24%

32%

0%

10%

20%

30%

40%

50%

60%

70%

PREVALENCE OF OBESITY

PREVALENCE OF NAFLD

Prevalence of NAFLD as a function of obesity indifferent part of the world From Lazo et al. Semin.Liver Dis., 2008 modified

• The prevalence of NAFLD in USA is 22%

• Patients with NAFLD have higher overall mortality than control patients

• Most deaths were due to cardiovascular events

• The independent predictors of mortality in patients with NAFLD are male sex, older age, increased waist circumference, and low high-density lipoprotein levels

• Serum alanine aminotransferase (ALT) levels and the presence of metabolic syndrome are not predictive of mortality

EPIDEMIOLOGY OF NAFLD IN USA

US NHANES III study: Lazo et al. Am.J.Epidemiol., 2012

35,781 primary LT in the US from 2001-20091959 for NASH

• NASH increased from 1.2% in 2001 to 9.7% in 2009• 3rd most common indication for LT in the US

Charlton, Gastroenterology 2011

Loomba R.J.Nat.Rev.Gastroenterol.Hepatol., 2013,

Country Diabetes (%) Obesity (%) Dyslipidaemia (%)

Japan 40-50 50-80 42-58

China 35 70-80 57

South Korea 35 10-50 26-35

India 39-90 15-20 Not reported

Indonesia 52 47 56

PREVALENCE OF NAFLD IN HIGH-RISKPOPULATIONS IN ASIA

Characteristic East West

Prevalence 10-20% 20-30%

Rural vs Urban Yes No

Prevalence of obesity Low but rising High

Prevalence in type 2 diabetes Higher Lower

NAFLD in those with normal weight

Higher Lower

Natural history data Limited data Cohort studies

Loomba R.J.Nat.Rev.Gastroenterol.Hepatol., 2013,

PREVALENCE OF NAFLD IN EAST AND WEST PART OF THE WORLD

PREVALENCE OF NAFLD IN EUROPE

Blachier A. et al J.Hepatol., 2013

COUNTRY Case Identific.

Prevalence NAFLD

Reference

14 EU Countries

FLI* 33% (adults) Gastaldelli et al. Hepatol., 2009

Germany US and LE 2% (36% in obese children)

Imhof et al., Eur.J.Epidemiol., 2007

Germany US 30% (adults) Haring et al., Hepatol., 2009

Greece Histology 31% (adults) Zois et al., WJG, 2010

Italy US 26% (adults) Bedogni et al., Hepatol., 2007

Italy US 12.5% (adolescents) Caserta et al., Am.J.Epidemiol., 2010

Italy US 44% (obese children) Sartorio et al., Eur.J.Clin.Nutrit., 2007

Italy US 69.5% (diabetic pts) Targher et al., Diabetes Care, 2007

Romania US 20% (adults) Radu et al., J.Gastroint.Liver Dis., 2008

Spain US 25.8% (adults) Caballeira et al., Eur.J.Gastroint.Hepatol., 2010

UK US 46.2% (diabetic pts) Williamson et al., Diabetes Care, 2011

* GGT, TG, BMI and WC

Prevalenza

FL = 58.3%

Fegato grasso nello studio Dionysos

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

PREVALENZA NELLA POPULAZIONE GENERALE IN ITALIA:

NAFLD = 25-30 %NASH = 2-3 %

PREVALENCE OF NAFLD:TAKE HOME MESSAGES

• General population :• 12-20% in children

• 20-33% in adults - average 25%• Increases with age; • Higher in males vs female; • Higher in Caucasian and Hispanic; • Not significantly higher in subjects with alteration of ALT vs normal

Selected population Prevalence of NAFLD/NASH is higher in:

Obese subjects (36-78%) Pts. with hyperglicemia or diabetes (43-62%) Pts. with hyperlipemia (45-65%) Pts. with hypertension (35-45%) Pts. with metabolic syndrome: the risk of

progression vs more severe stages of chronic liver disease is significantly increased

Pts. with HCV infection (55%) NAFLD is associated to insulin-resistence

and is now considered the hepatic manifestation of the metabolic syndrome

PREVALENCE OF NAFLDTAKE HOME MESSAGES

Incidence of NASH in living liver donors according to liver enzymes

(n= 589)

Normal

Mild steatosis

SeveresteatosisNASH

Lee JY, J. Hepatol. 2007

Normal AST, ALT

Raised AST, ALT

NASH: 2.1%

NASH: 3.4%

INCIDENCE OF NASHTAKE HOME MESSAGES

• By extrapolation of data available in autopsy and liver biopsy studies (few !!):

• 10-15% of people with NAFLD, equivalent to 2-4% of the general population may have NASH, thus a progressive chronic liver disease to cirrhosis and HCC

NASH Non Alcoholic Steatohepatitis

ASH Alcoholic steatohepatitis

BASH Both alcoholic and non alcoholic steatohepatisis

DASH Drug induced steatohepatitis

CASH Chemotherapy associated steatohepatitis

PASH PNPLA3 associated steatohepatitis

Similar entities: differential diagnosis

PASH

NAFLDNASH

ASH

Alcoholiccirrhosis

Cryptogeniccirrhosis

Progressivefibrosis

ALT

PNLPA3 associated steatohepatis (PASH)

No obesity/overweightNo Insuline resitanceNo EtOH eccess

Disease Study YearNASH Romeo et al 2008

EtOH livercirrhosis

Tian et al 2010

HBV steatosis

Vigano’ et al 2013

HCV steatosis

Cai et al 2011

HCC Nichalker 2011

Carrier of the p.148M allele are at increasedrisk of severe hepatic phenotype

Risk factor for NAFLD/NASH are similar in all countries:

The most documented one is obesity (BUT 30% of obese have not NAFLD) especially visceral obesity (WC)Age > 45 (risk factors increase with age)Male sexHypertensionHyperlipidaemiaDiabetes type 2 or IRMetabolic syndromeFructose in the dietGrade of inflammation at initial biopsy

Risk factors for NAFLD/NASH

Lonardo A, Bellentani S, et al., DLD 2015, in press

Lonardo A, Bellentani S, et al., DLD 2015, in press

Il piu’ documentato e’ l’obesità viscerale (WC): 30% degli obesi ha NAFLD; Età > 45 Sesso maschile Ipertensione Iperlipidemia Diabete tipo 2 o IR Sindrome metabolica Grado di infiammazione alla biopsia iniziale Fruttosio nella dieta

Fattori di rischio per NAFLD/NASH

HFCS consumptionEnergy consumption of fructose from sweetened beverages in patients with NAFLD wasestimated as 356 kcal /day compared with 170 kcal /day in control patients with non -steatoticlivers (p<0.05).

Ouyang X et al. J.Hepatol., 2008

Industrial, not Fruit Fructose Intake is Associated with the Severity of Liver Fibrosis in Genotype 1 Chronic Hepatitis C PatientsSalvatore Petta, Giulio Marchesini, Linda Caracausi, Fabio Salvatore Macaluso, Calogero Cammà, Stefania Ciminnisi, Daniela Cabibi, Rossana Porcasi, Antonio Craxì, Vito Di Marco

J.Hepatol., 2013

CVD T2DM

de Alwis and C Day, J Hepatol, 2008, S104

??

“Le evidenze attuali suggeriscono di mettere in atto pela NAFLD strategie di monitoraggio per le malattie cardiovascolari. I pazienti con NAFLD, specialmente quelli con NASH, sono candidati ad un precoce ed aggressivo trattamentnon solo della loro epatopatia ma anche dei rischi associati di MCV, perchè molti di loro svilupperanno in futuro eventi CV maggiori o moriranno di MCV prima chsi sviluppi una cirrosi epatica o un HCC.”

Targher et al., NEJM, 2010

Targher et al Diabetes Care 2007

2,839 T2DM

81.5%: NAFLD (Ecografia)

NAFLD vs non-NAFLD

(p<0.001):

-↑ malattia coronarica

(26.6 vs. 18.3%)

- ↑ malattia cerebrovascolare

(20.0 vs. 13.3%)

- ↑ vasculopatia periferica

(15.4 vs. 10.0%)

La NAFLD è un fattore di rischio cardiovascolareindipendentemente dal T2DM

NAFLD E MCV : SUMMARYL’insulino resistenza “per se” è sufficiente per indurre dislipidemia e aterosclerosi nell’animale sperimentale.Nell’uomo la NAFLD è associata con:1- Disfunzione dell’ endotelio vascolare2- Alterazione dei markers surogati di aterosclerosi3- Alterazione del metabolismo energetico del ventricolo sinistro4- Aumeto della espressione di mediatori dell’infiammazione

Ratziu V, Bellentani S et al. EASL NAFLD/NASH Position Paper J.Hepatol., 2010

TAKE HOME MESSAGES• Given the strong association of NAFLD with

metabolic syndrome and the worldwide epidemic of obesity, the prevalence of NAFLD and NASH are increasing (Public health issue)

• NAFLD warrants screening for cardiovasculardiseases (proved increased mortality !!) and progressive liver disease

• 10-15% of people with NAFLD ( 2-4% of the general population) may have NASH, thus a progressive chronic liver disease leading to cirrhosis and HCC

NAFLD wide spectrum ranging from fatty liver to nonalcoholic steatohepatitis(NASH) that may progress to cirrhosis and end-stage liver disease.

THE BURDEN OF NAFLD/NASH AND NASH-RELATED CIRRHOSIS AND PREVALENCE OF HCC

IN THE GENERAL POPULATION

CLINICAL PATTERNS OF HEPATOCELLULAR CARCINOMA (HCC) IN NON ALCOHOLIC FATTY LIVER DISEASE (NAFLD): A MULTICENTER

PROSPECTIVE STUDYFabio Piscaglia, Gianluca Svegliati-Baroni, Andrea Barchetti, Anna Pecorelli, Sara Marinelli, Claudio Tiribelli and Stefano Bellentani, on behalf of the HCC-NAFLD ItalianStudy group (Hepatology, 2015: revised version submitted)

756 patients with either HCC-NAFLD (145) or HCC-HCV (611) were enrolled in Secondary Care Italian Centers

RESULTS HCC-NAFLD vs HCC-HCV: 1- Significantly volume, more often an infiltrative pattern

2- Cirrhosis was present in only about 50% vs 95% in HCC-HCV

3- Survival was significantly shorter (p=0.017), namely 25.5 months (95% CI 21.9-29.1) vs 33.7 months (95% CI 31.9-35.4) in HCC-HCV.

4- Propensity score analysis showed no more significant difference.

5- Additionally, did not show No difference in survival between the 2 groups (38.6 vs 41.0 months, p=n.s.) in patients within Milan criteria

Survival curves of patients with NAFLD-HCC VS HCV-HCC in the Early Stage (Milan in) submitted to curative treatments

CLINICAL PATTERNS OF HEPATOCELLULAR CARCINOMA (HCC) IN NON ALCOHOLIC FATTY LIVER DISEASE (NAFLD): A MULTICENTER

PROSPECTIVE STUDYFabio Piscaglia, Gianluca Svegliati-Baroni, Andrea Barchetti, Anna Pecorelli, Sara Marinelli, Claudio Tiribelli and Stefano Bellentani, on behalf of the HCC-NAFLD ItalianStudy group (Hepatology, 2015: revised version submitted)

HCC-NAFLD : Specific Distinct Features1. The tumor develops in the context of well-known metabolic

and lifestyle risk factors (and with a genetical component).

2. The tumor is strictly associated with metabolic diseases(obesity, diabetes, etc.), but not neccessarly with thepresence of cirrhosis (40%)

3. The survival of treated HCC-NAFLD is similar to treatedHCC-HCV.

4. Prevention and surveillance strategies for HCC-NAFLD arelacking

5. The current guidelines for the management of HCC have nospecific raccomendations for HCC associated with NASH

GRAZIE PER L’ATTENZIONE !Stefano Bellentani, MD, PhDbellentanistefano@gmail.com