Amedeo Lonardo - ?· Amedeo Lonardo Reggio Emilia, 31ottobre 2012 •RIVEDERE CRITICAMENTE ... Metaboliche-Genetiche…

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Responsabile DH Epatologico - Internistico

NOCSAE - OSPEDALE DI BAGGIOVARA MODENA

Amedeo Lonardo

Reggio Emilia, 31ottobre 2012

RIVEDERE CRITICAMENTE LUTILITA E I LIMITI DELLE TRANSAMINASILE INDICAZIONI ALLECOGRAFIA EPATICALA PRATICA DELLA BIOPSIA EPATICANOTIZIE UTILI ALLA GESTIONE DELLEPATOPAZIENTE:

NAFLD EPATITE CRONICA TERAPIA CIRROSI HCC

OBIETTIVI DEL CICLO DI LEZIONI

Metodo di lavoro interattivo

E-mail: a.lonardo@ausl.mo.it

-Domande specifiche-Casi clinici-Lavoro per piccoli gruppi

Calendario dei lavori

31 Ottobre NAFLD7 Novembre Epatiti croniche virali21 Novembre Terapia Cirrosi28 Novembre HCC

NAFLD

Reggio Emilia, 31 ottobre 2012

Non Alcoholic Fatty Liver Disease (NAFLD)

HCC

Le contraddizioni di un nomeal negativo..

Nulla osta che un paziente, ad esempio obeso, abbia una NAFLD, ma anche unAFLD (ASH&NASH).

Oppure che abbia uninfezione da HCV

e anche una NAFLD..

(Sderberg HEPATOLOGY 2010;51:595-602.)

STEATOSIS

NASH

PATHOGENESIS OF NAFLD

Familial Susceptibility Unbalanced diet

Sedentariety

Kang H Am J Gastro 2006

Abdelmalek. Clin Gastro Hepatol 2006

Hsieh SD, Circulation. 1998

Sandoval, R J Seeley Science 2010;328:179-180

Relationship between hepatic fat accumulation and insulin resistance in NAFLD

( Donnelly KL J Clin Invest. 2005 May;115:1343-51)

Fig. 4

METABOLIC SYNDROMEINSULIN RESISTANCE

GENETICSLipidomic signature

NASHNASH-cirrhosis

End-stage Liver failureHCC

AtherosclerosisExcess mortality

Pure SteatosisIMT

Normal life expectancy

Normal adaptive responsegood storer

Failed adaptive responsebad storer

LIFESTYLE Diet

High saturated fatsfructose

Low antioxidants

SedentarietyGENETIC ANDHORMONALFACTORS

Gene POLYMORPHISMSHORMONAL FACTORSMICRORNAs profile

One Hit Theory on Pathogenesis and Natural History of NAFLD

HCV

Adipose tissue

Free Fatty Acids

Liver

De novo lipogenesisMitochondrial Oxidation

Export oflipoproteins

Insulin resistance,Cytokines, direct effect ?

Lonardo, Adinolfi, Loria Hot Topics Viral Hepatitis 2009

IRMetS

Type 2 DIABETES

HYPERTENSION

ATHEROGENIC DYSLIPIDEMIA

Central OBESITY

The galaxy of the Metabolic Syndrome of Insulin res istance

NAFLD

Prothrombotic State

Cholesterol Gallstones OTHERS?

Hyperuricemia

Hyperferritinaemia

Colon Cancer

Obstructive Sleep ApneaSyndrome

Progressive Renal DiseaseRheumatological disease

Erectile Dysfunction

Macrovascular Disease

Lonardo, Caldwell Loria. Expert Review 2010

THE DEADLY QUARTET

ABDOMINAL OBESITY

ATHEROGENIC DYSLIPIDEMIA

ARTERIALHYPERTENSION

HYPERGLYCEMIA

iperglicemia

T G ; HDL

ponderale

transaminas i

ipertens ione

Danno vascolare

Ultima tappa ?

ADOL E S C E NZ A G IOVINE ZZA-E TA ADUL TA-MATUR ITA VE C C HIAIA

STORIA NATURALE DELLINSULINORESISTENZA

Modificato da Suzuki & Angulo Hepatology 2005

Ryan MC Diabetes Care 2005

Association between severity of the Metabolic Syndrome and liver fibrosis in

NAFLD

1952 Zelman pubblica il Fegato dellobeso1954 Dianzani descrive la disfunzione mitocondriale nella steatosi1962 Thaler descrive quella che oggi chiamiamo NASH1965 Di Luzio usa gli antiossidanti contro la steatosi sperimentale1973 Itoh descrived five diabetic non-alcoholic women with micronodular

cirrhosis tutte ultra50enni obese. 1980 Ludwig conia il nome Nonalcoholic steatohepatits1985 Batman propone lesistenza di una Diabetic hepatitis1988 Diehl descrive Alcohol-like liver disease in the non-alcoholic1997 Lonardo riporta laSindrome del fegato iperecogeno1999 Mendler propone Insulin-resistance associated hepatic iron overload.

Nello stesso anno diversi Autori propongono che la NAFLD sia manifestazione epatica di S. da insulinoresistenza e Brunt una classificazione istologica ancora in uso

2000 Falk Symposium NASH & ASH (LAia)2002 AGA technical review on nonalcoholic fatty liver disease 2003 Monotematica AASLD2005 Nuova Classificazione istologica2006 EASL monothematic Conference (Lisbona)2010 EASL monothematic Conference + Guidelines italiane NAFLD

Principali tappe nello sviluppo della NAFLD

Practice guidelines for the diagnosis and management of NAFLD.A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee

The present guidelines consist of 10 issues (decalogue) including:

(1) Introduction and methodology; (2) Prevalence, incidence and natural history; (3) NALFD, HCV and the metabolic syndrome;(4) Diagnosis; (5) Differential diagnosis with alcoholic liver disease;(6) Treatment; (7) Follow-up; (8) Prevention; (9) NAFLD and orthotopic liver transplantation (OLT);(10) Research agenda.

2.1. Prevalence of primary NAFLD/NASH

The prevalence of NAFLD in general populationin Western countries, including Italy, is about 25%.The prevalence varies as a function of age, gender and ethnicity.

Level of evidence: I

According to the best available evidence the prevalence of NASH in USA lean subjects is 2.7%,a figure in the same order magnitude reported for hepatitis C (Table).

Level of evidence: IIIII

La NAFLD di gran lunga lepatopatia pi frequente

Eziologia dellepatopatia Prevalenza*NAFLD 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 1-antitripsina 1/1500-1/7600Malattia di Wilson 1/30.000

* Popolazione generale, USA

CLASSIFICAZIONE NAFLD

PRIMARIA

SECONDARIA

Nutrizionale (Malnutrizione, chirurgia bariatrica NPT)

Endocrina (Ipotiroidismo, PCOS, etc)

Da Farmaci (Glicocorticoidi, Tetraciclina, Metotrexato etc)

Metaboliche-Genetiche (Ipobetalipoproteinemia)

Altre (IBD, HIV, Petrolchimici)

NAFLD ENDOCRINE

Lonardo A. et al. / J Hepatol 2006;44:11961207

NASH ENDOCRINE

Loria, Carulli, Bertolotti e Lonardo Nature Clinica l Practice Gastro Hepatol 2009

2.1. Prevalence of primary NAFLD/NASH

Elevated ALT levels do not discriminate NAFLD either from normal liver or from alcoholic fatty liver disease (AFLD) since liver enzymes are normal in almost half of NAFLD cases.

Studies have also shown that normal ALT values do not rule out NASH and fibrosis.

Level of evidence: ILevel of evidence: I

THE MEAN (SD) GRADE OF THE INDIVIDUAL HISTOLOGIC FINDINGS OF NAFLD IN 51 SUBJECTS

WITH NAFLD AND NORMAL ALT (BLACK) AND 50 SUBJECTS WITH NAFLD AND ELEVATED ALT LEVELS (DOTTED ).

Clinica Chimica Acta 1957; 2:7074

Clinica Chimica Acta 1957; 2:7074

Clinica Chimica Acta 1957; 2:7074

Context

Current upper limits ( [30 U/L] for women, [40 U/L] for men ) for serum alanine aminotransferase (ALT) level were defined in populations that included persons with nonalcoholic fatty liver disea se (NAFLD) and persons with hepatitis C virus (HCV) infection.

Contribution

This study redefined ALT limits in blood donors at l ow risk for NAFLD and without hepatitis B or C ( [19 U/L] in women, [30 U/L] in men ). When applied to 209 anti-HCVpositive donors, the ne w thresholds had 76.3% sensitivity and 88.5% specificity in iden tifying patients with hepatitis C viremia compared with 55% and 97.4% for ol d thresholds.

Implications

Laboratories should consider revising the upper limits o f normal for ALT to improve the sensitivity of this test in iden tifying subclinical liver disease .

BMI, DRUGS AND PAINTS ARE ASSOCIATED WITH

TRANSIENT (+-) ELEVATION OF AMINOTRANSFERASE LEVELS

Morisco F, et al DLD 2009

MALE GENDER, ALCOHOL INTAKE > 27 g/DAY AND BMI > 25 Kg/m2 ARE ASSOCIATED WITH PERSISTENTLY ALTERED LIVER TESTS IN VIRUS-FREE INDIVIDUALS

PENDINO, HEPATOLOGY 2005;41:1151-1159

INDEPENDENT FACTORS ASSOCIATED WITH CAROTID INTIMA-MEDIA THICKNESS.

Kim, Di a b e t e s R e s C l i n P r a c 2 0 1 0

Methods: This was an observational study performed on 830 healthy individuals with normal ALT concentration (40 U/L). Atherosclerotic burden was assessed by carotid arterial intima-media thickness (IMT). All subjects were divided according to the quartile based on their ALT concentrations.

Results: Despite all subjects having a normal ALT concentration, ultrasonographic liversteatosis was observed in 48.4% of men and 36.7% of women. In both genders, subjects in the highest quartile of ALT concentration had a a significantly higher waist circumference, triglyceride concentration, HOMA-IR, a higher prevalence of metabolic syndrome, and a greater severity of ultrasonographic liver steatosis than did those in the lower quartiles. In women, the carotid IMT increased significantly with increasing quartiles of ALT concentration (0.62 0.14 mm, 0.66 0.15 mm, 0.69 0.15 mm, vs. 0.72 0.24 mm; P for trend < 0.001). Based on multivariate regression analysis, the serum ALT, even within the normal range, was associated with the carotid IMT in both men and women, and independently of traditional cardiovascular risk factors.

Conclusions: ALT concentrations, albeit within the reference range, were associated with atherosclerotic burden in healthy adults.