Download pdf - Amedeo Lonardo - ASMNbiblioteca.asmn.re.it/allegati/epatopatie_130713113525.pdf · Amedeo Lonardo Reggio Emilia, 31ottobre 2012 •RIVEDERE CRITICAMENTE ... Metaboliche-Genetiche

Responsabile DH Epatologico - Internistico

NOCSAE - OSPEDALE DI BAGGIOVARA – MODENA

Amedeo Lonardo

Reggio Emilia, 31ottobre 2012

•RIVEDERE CRITICAMENTE L’UTILITA’ E I LIMITI DELLE TRANSAMINASILE INDICAZIONI ALL’ECOGRAFIA EPATICALA PRATICA DELLA BIOPSIA EPATICANOTIZIE UTILI ALLA GESTIONE DELL’EPATOPAZIENTE:

� NAFLD � EPATITE CRONICA� TERAPIA CIRROSI� HCC

OBIETTIVI DEL CICLO DI LEZIONI

Metodo di lavoro interattivo

E-mail: [email protected]

-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 nome“al negativo”…..

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

• Oppure che abbia un’infezione da HCV

e anche una NAFLD…..

(Söderberg 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 response“good storer”

Failed adaptive response“bad 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 lipogenesis↓Mitochondrialβ 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 DELL’INSULINORESISTENZA……”

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 dell’obeso”1954 – 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 steatohepatits”1985 – Batman propone l’esistenza di una “Diabetic hepatitis”1988 – Diehl descrive “Alcohol-like liver disease in the non-alcoholic”1997 – Lonardo riporta la“Sindrome del fegato iperecogeno”1999 – 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” (L’Aia)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: II–III

La NAFLD è di gran lunga l’epatopatia più frequente

Eziologia dell’epatopatia 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 α1-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;44:1196–1207

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; 2:70–74



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-HCV–positive 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.

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

Livelli transaminasemici nelle epatopatie di diversa eziologia

RICOVERO

AMBULATORIO

2.3. Natural history

Whilst pure steatosis is not associated with excess mortality in long-term follow-up studies, individuals with NASH have a reduced life expectancy. Recent evidence suggests that, further to liver-related death (due to end-stage liver failure, complications of portal hypertension and HCC), patients are exposed to increased frequency of cardiovascular diseases leading to excess mortality. Middle-aged adults may be at particularly high risk.

Patients with either uncomplicated fatty liver or NASH appear to be at risk of developing the full-blown metabolic syndrome or its individual components, particularly type 2 diabetes and impaired fasting glucose .

3. NAFLD, HCV and the metabolic syndrome

Steatosis is present, on average, in 55% of cases of chronic HCVinfection . The prevalence and the extent of steatosis vary as a function of viral (genotype) and host factors.Genotype 3 is directly steatogenic. In genotype 1, steatosis is associated with the features of the metabolic syndromesuch as insulin resistance, increased BMI and visceral obesity, and ethnicity. Additional host’s genetic features may increase the risk of developing steatosis in those infected with HCV.

Level of evidence: I–III

Although insulin resistance is present both in NAFLD and in HCV-associated steatosis in a high proportion of cases (>70%), in comparative studies the metabolic syndrome is more prevalent amongst NAFLD patients (41–52%) than amongst those with HCVassociated steatosis (4.4–25%).

Level of evidence: III

3. NALFD, HCV and the metabolic syndrome

Irrespective of genotype, HCV-associated steatosis is a risk factor for fibrosis progression in cross-sectional and prospective studies.Moreover, steatosis is a risk factor for the developmentof HCCin patients with chronicHCVinfection, with or without cirrhosis.


HCV-associated steatosis is linked with a lower sustained response rate to treatment with Peg-interferon (Peg-IFN) and ribavirin (RBV) in genotype 1-infected patients and increased relapse rate in individuals with genotypes 2 and 3 . The response to Peg-IFN and RBV is lower in patients with a high BMI and elevated insulin resistance. In chronic HCV infection, BMI and IR are risk factors for steatosis and fibrosis. Therefore, the reduction of overweight and IR constitutes an additional rational therapeutic strategy in the treatment of chronic hepatitis C.

Level of evidence: IIIStrength of recommendation: A

4. DiagnosisFig. 2 illustrates an integrated diagnostic and therapeutic flowchart which

can be applied in clinical practice.

4.2. Clinico-laboratory evaluation

A complete personal and familial medical historyshould be taken, directed at evaluating and recording the risk factors for NAFLD, alcohol consumption and lifestyle. In young women, changes in the menstrual cycle and hirsutism may suggest the presence of polycystic ovary syndrome, frequently associated with NAFLD.A complete physical examination should be performed, including measurement of height, weight, abdominal circumference,waist-to-hip ratio, and arterial pressure.

Strength of recommendation: A

MISURAZIONE DEL GIRO VITA

ESAME OBIETTIVO MISURAZIONE VITA

GRUPPO ETNICO CIRCONFERENZA VITAEuropei

Americani

Maschi ≥ 94 Femmine ≥ 80

Maschi≥ 102 Femmine ≥ 88

Asiatici meridionali Maschi ≥ 90 Femmine ≥ 80

Cinesi Maschi ≥ 90 Femmine ≥ 80

Giapponesi Maschi ≥ 85 Femmine ≥ 80

Sud- Centro-Americani come asiatici meridionali finchè avremo piu’specifiche raccomandazioni

Africani del sub-sahara e

Arabi del mediteraneo orientale/medio oriente

Come per gli europei finchè avremo piu’specifiche raccomandazioni

Alberti, Zimmet, Shaw, Diabetic Medicine 2006

Specific issues to be addressed in history taking, performing physical examination and selecting laboratory tests.

QUANTO ALCOL E’ EPATOTOSSICO?

… 3 verres par jour pour l’homme, 2 pour la femme…

PREDITTORI DI FIBROSI NELLA NASH

BARD BARG BAAT HAIR Angulo ‘05 Angulo ‘07

BMI SI’ SI’ SI’ -- SI’ SI’

ETA’ SI’ -- SI’ -- SI’ SI’

AST/ALT SI’ SI’ -- -- SI’ SI’

ALT -- -- SI’ SI’ -- --

ALBUM. -- -- -- -- SI’ --

Piastrine -- -- -- -- SI’ SI’

DT2 SI’ -- -- -- -- --

HbA1c/glic. -- SI’ -- -- SI’ SI’

IR index -- -- -- SI’ -- --

TG -- -- SI’ -- -- --

IPERTEN. -- -- -- SI’ -- --Modificato da: Farrell Hepatology 2006 S99-112

4.5. Role of imaging studies4.5.1. Ultrasound scanning

The advantages of ultrasound scanning of the liver include safety, low cost and repeatability . Based on these characteristics, ultrasonography is the first-line imaging technique suitable bothin the clinical settingand for epidemiological studies.

Level of evidence: IStrength of recommendation: A

Limitations of the technique include the relatively low sensitivity in detecting minor degrees of fatty changes, the low accuracy in the obese and meteoric patient, the inability to differentiate simple steatosis from NASH and the operator-dependency.At ultrasound scanning, signs of liver steatosis are the presence of a bright echo pattern of the liver, posterior attenuation and/or skip areas. These are closely related to fatty changes ≥20–30%.

Level of evidence: IIIStrength of recommendation: B–C

Ultrasound Fatty Liver Index (US-FLI)

• Score ecografico semiquantitativo che varia da 2 to 8. • Condizione “Sine qua non”per la diagnosi di steatosi è la

presenza di contrasto epatorenale, mild/moderate (score 2) o severa (score 3).

• Criteri aggiuntivi (1 punto ciascuno):– attenuazione posteriore del fascio ultrasonoro,– difficile visualizzazione di

• Vasi• parete colecistica • diaframma

– aree di risparmio focale “focal sparing”.

La diagnosi ecografica di steatosi si basa sul punteggio minimo di 2.

(Carulli L, J Hepatol 2008)

SEMEIOTICA -US-FLI

Major criteria liver-kidney contrast: 0/2/3

Minor criteria posterior attenuation of ultrasound beam: 0/1

reduced visualization of the diaphragm: 0/1vessels blurring: 0/1

reduced visualization of the gallbladder wall: 0/1focal sparing: 0/1

US-FATTY LIVER INDICATOR (total): 0/2-8

US-FLI < 4 Esclude NASH0.

000.

250.

500.

751.

00S

ensi

tivity

0.00 0.25 0.50 0.75 1.001 - Specificity

Area under ROC curve = 0.7635

AUC 0.7635 (95% CI: 0.634-0.893) P=0.0020.

000.

250.

500.

751.

00S

ensi

tivity

0.00 0.25 0.50 0.75 1.001 - Specificity

Area under ROC curve = 0.7960

AUC 0.796 (95% CI: 0.676-0.916) P=0.000NAS scoreBrunt

Ballestri, Lonardo, et al. Liver Intern 2012

INDICAZIONI AD ECOGRAFIA EPATICA

Paziente asintomaticoScoperta occasionale di epatomegalia

alterate ALT AST GGTCheck-periodici o assicurativiDismetabolismi glicolipidici, spt. DT2 Diagnosi precoce di HCCFollow-up di neoplasia notaFamiliarità per epatopatieDesiderio del paziente

Paziente sintomaticoCalo ponderaleDispepsiaAsteniaSintomi suggestivi di epatopatia (ittero, ascite, prurito)

4.5.2. Computed tomography scanning

Computed tomography (CT) enables the evaluation of the liverto- spleen attenuation ratio that correlates with the degree of steatosis on histopathology. Patients withNASHhave a greater liver span and increased caudate-to-right-lobe-ratio compared with patients with steatosis alone. CT scanning, however, exposes patients to ionising radiation, thus its use is not recommended,particularly in the paediatric population and in follow-up studies.

Level of evidence: IIIStrength of recommendation: D

4.5.3. Magnetic resonance imaging

Although probably the most accurate and fastest method of detecting liver fat, magnetic resonance (MR) spectroscopy is expensive.

Moreover, the necessary software is not available in most MRImaging Units. MR elastography, a new technique to assess liverstiffness, has not been demonstrated to detect NAFLD. MRItechniques are expected to become useful tools in future studies,either in examining the natural history of NAFLD, or in testing new treatment results .

Level of evidence: IIIStrength of recommendation: B

Szczepaniak 2004

Measurement of hepatic TG content by proton magnetic resonance spectroscopy

50-100 mg 27 g27 grammi

4.6. Transient elastography (FIBROSCAN)

Transient elastography measures liver stiffness which is correlated with fibrosis stage in NASH. Transient elastography is, however, influenced by elevated ALT, steatosis and is limited by technical problems in abdominal obesity.

Level of evidence: IIIStrength of recommendation: B

Reliability of transient elastography for the detection of fibrosis in

Non-Alcoholic Fatty Liver Disease and chronic viral hepatitis.

• METHODS: TE was performed in 219 consecutive patients with chronic liver disease (35% CHC, 32% CHB, and 33% NAFLD) within 6 months of the liver biopsy. RESULTS: LSM was related to the fibrosis stage in each group (CHC: p = 0.596, p < 0.001; CHB: p = 0.418, p < 0.001; NAFLD: p = 0.573, p < 0.001), but the correlation was less strong in CHB and NAFLD than in CHC patients. In CHB patients with histological cirrhosis (F4), the median stiffness value was almost two times lower than in patients with severe fibrosis (F3). In NAFLD patients with advanced fibrosis (F3) and severe steatosis (> 33%), the LSM values were lower than expected and were similar to those of patients with initial fibrosis (F1) and fat < 33%. TE underestimated the stage of fibrosis in 75% of patients with F3 and steatosis > 33%.At multiple logistic regression analysis, in CHC and CHB patients, LSM was the only predictive variable of severe fibrosis/cirrhosis (OR = 1.42, p = 0.003 and OR = 1.354, p = 0.003, respectively), while in NAFLD subjects BMI and AST (OR = 1.433, p = 0.002 and OR = 1.053, p = 0.020, respectively) but not LSM were independently related with advanced fibrosis and cirrhosis.

• CONCLUSIONS: This study confirms that TE can be considered a valid support to detect fibrosis in chronic liver disease related to HCV but it should be interpreted cautiously in CHB and NAFLD patients, where host or disease-related factors may modify its accuracy.

Gaia S J Hepatol. 2011 Jan;54(1):64-71.

Abbreviations: A1-AT, alpha1-anti-trypsin disease; AIH, autoimmune hepatitis; AMA, antimitochondrial antibody; DILl, drug-induced liver injury; HCC, hepatocellular carcinoma; NAFLD/NASH, nonalcoholic fatty liver disease/nonalcoholic steatohepatitis; OLT, orthotopic liver transplantation; PBC, primary biliary cirrhosis; PSC, primarysclerosing cholangitis.

Use of Liver Biopsy

Rockey, HEPATOLOGY, Vol. 49, No. 3, 2009

Absolute

Uncooperative patient

Severe coagulopathy

Infection of the hepatic bed

Extrahepatic biliary obstruction

Relative

Ascites

Morbid obesity

Possible vascular lesions

Amyloidosis

Hydatid disease

Contraindications to Percutaneous Liver Biopsy

Rockey, HEPATOLOGY, Vol. 49, No. 3, 2009

COMPLICATIONS OF LIVER BIOPSY

BLEEDING , MAJOR(requiring transfusion/intervention)

1 in 2500 to 1 in 10,000 biopsies

BLEEDING , MINOR(not requiring transfusion/intervention)

1 in 500 biopsies

DEATH 1 in 10,000 biopsies

OTHERSpneumothorax, hemothorax, perforation of any of several viscous organs, bile peritonitis, infection (bacteremia, abscess, sepsis), hemobilia, neuralgia,

5. Differential diagnosis with alcoholic fatty liver disease

In clinical practice, however, given its common occurrence, the differentiation of NAFLD from AFLD remains a challenge, which can be faced utilising patient interview coupled with laboratory findings.

Occult alcohol abuse should be ruled out in subjects with fatty liver disease, particularly in elderly males.Level of evidence: II–IIIStrength of recommendation: A

The threshold for hepatotoxicity in a free-living population in Italy is 30 g/die . An Italian Expert Panel suggested 20/30 g daily (women/men) as the level of “moderate alcohol consumption”, to be consumed during meals, and not to be exceeded This threshold is also acknowledged in clinical practice to differentiate AFLD from NAFLD.Level of evidence: IIIStrength of recommendation: A


The potential of modest alcohol consumption (<70 g/week) being associated with a reduced risk of increased transaminases and steatosis in patients without other liver conditionsneeds to be evaluated in additional studies before it can be translated in clinical practice.Level of evidence: III–IVStrength of recommendation: D


Not only the amount of alcohol consumed, but also the composition of the diet and the pattern of drinking are important determinants in the risk of liver disease. Drinking on an empty stomach and/or drinking multiple types of alcoholic beverages, independent of the amountdrunk is associated with an increased prevalence of alcoholic liver disease.Advice for hepatological lower-risk drinking habits should take into account the results of the above studies.Level of evidence: III–IVStrength of recommendation: A

Obese subjects are likely to be exposed to more severe alcoholhepatotoxicity. Obese subjects should be discouraged from drinking alcohol.Level of evidence: IV–VStrength of recommendation: A

BRUNTGrado Steatosi Balloning FlogosiLIEVE 1-2 Minimo Lobulare 1-2

Portale 0-1MODERATO 2-3 Presente Lobulare 2

Portale 1-2

SEVERO 3 Marcato Lobulare 3

Portale 1-2

Stadio 1 Zona 3 perivenulare, perisinsoidale o pericellulare; focale o esteso

Stadio 2 CS + fibrosi portale (focale o estesa)

Stadio 3 Fibrosi a ponte, focale o estesa

Stadio 4 Cirrosi

Brunt Am J Gastroenterol 1999; Neuschwander, Hepatology 2003

KLEINER

STEATOSI FLOGOSI

LOBULARE

BALLONING

0 = < 5 % 0 = assente 0 = assente

1 = 5-33% 1 = < 2 foci x 200 campi 1 = Poche cellule

2 = 34-66% 2 = 2-4 foci x 200 campi 2 = Molte cellule/prominente

3 = > 66% 3 = > 4 foci x 200 campi

NAFLD ACTIVITY SCORE

DIAGNOSI ISTOLOGICA

DI NASH

≥5 Probabile o sicura

3-4 Incerta

≤ 2 Non NASH

Hepatology 2005


Table 6 summarises the characteristics of currently used biomarkers of alcoholism.Owing to alcohol’s short half-life serum and urine alcohol levels cannot be utilised for the diagnosis of alcoholic liver disease. The combination of physician interview, questionnaire and laboratory markers is necessary for the diagnosis of alcoholism.The most sensitive and specific of the commonly used biomarkers of alcohol intake are carbohydrate-deficient transferrin (CDT) and the combination of GGT and CDT .One of the postulated advantages of CDT over many other markers is that it is notinfluenced by the presence of liver disease. CDT alone or combined with GGT is more sensitive in males than in females, in those older than 35 years of age and in those who drink more than 60 g alcohol per day.Level of evidence: II–III

CDT is the only test approved by the FDA for the identification of heavy alcohol use. Its use in this specific subset of individuals is recommended although the procedure is not widely available.Level of evidence: III–IVStrength of recommendation: B

Marker Abbreviation

Half-life/ elimination rate

Clinical characteristics

Blood ethanol

EtOH 1 g/1 h/10 kg

Levels exceeding 1.5‰ without evidence of intoxication or 3‰ at any time indicate ethanol tolerance typically found in alcohol abusers and alcohol-dependent patients. Suitable for emergency clinics.

Gamma-glutamyltransferase

GGT 2–3 weeks A sensitive and inexpensive marker. Age-dependent. specificity decreased by obesity, diabetes, nonalcoholic liver diseases, pancreatitis, hyperlipidemia, cardiac insufficiency, severe trauma, medications (barbiturates, drugs for epilepsy, anticoagulants), nephrotic syndrome, renal rejection.

Mean corpuscular volume of erythrocytes

MCV2–4 months

More sensitive in women. Specificity decreased by vitamin B12 or folic acid deficiency, liver diseases, haematological diseases, hypothyroidism, reticulocytosis, smoking.

BIOMARKERS IN ALCOHOLISM

Marker Abbreviation

Half-life/elimination rate

Clinical characteristics

Carbo-hydrate-deficient transferrin

CDT(desialo-transfer-rin)

2–3 weeks

Most specific of the currently available methods. Specificity decreased by genetic variants of transferrin on rare occasions.

GGT–CDT combination

GGT–CDT (G-CDT)

2–3 weeks

A mathematically formulated combination, which is easy to manage in hospital laboratories. Improves sensitivity without a loss of specificity. Good correlation with the amount of recent ethanol intake. Suitable for routine use.

Aminotransferases

AST, ALT

2–3 weeks

AST/ALT-ratio over 2 suggests alcoholic aetiology in liver disease patients.

BIOMARKERS IN ALCOHOLISM


Due to the lack of specificity, GGT is a poor marker when alcohol consumption needs to be screened in patients with NAFLD or other liver diseases and in hospitalised patients. The test is not recommended in the differential diagnosis of alcoholic liver disease.Level of evidence: III–IVStrength of recommendation: D

Macrocytosis is not specific but there is a dose dependent response between erythrocytes and the amount of ethanol intake.Level of evidence: V

Thrombocytopenia is one of the most common laboratoryabnormalities in alcoholic patients.Level of evidence: VI

6. Treatment6.1. Non-pharmacologic treatment—lifestyle changes

Non-pharmacologic interventions aimed at correcting unhealthy lifestyles simultaneously treat all the clinical manifestations of the metabolic syndrome, and are an effective treatment option in NAFLD. Lifestyle changes include weight loss, dietary changes, reduction of sedentarity and physical exercise.

They are best accomplished through cognitive-behaviour therapy,which should always be implemented as first-line therapeutic option, regardless of the severity NAFLD/NASH.Level of evidence: IIStrength of recommendation: A

6.1. Non-pharmacologic treatment—lifestyle changes

The diet of NASH patients is richer in saturated fats and cholesterol and poorer in poly-unsaturated fats, fibers and antioxidants (vitamin C and E). A link was suggested between fructose overconsumption, dyslipidemia, insulin resistance and ectopic lipid deposition.All NAFLD patients should receive counselling for a low carbohydrateand low saturated fat diet, avoidance of fructose-enriched soft drinks and increased consumption of fruits and vegetables. Overweight individuals and those with visceral obesity should follow a hypocaloric diet aimed at 0.5 kg/week weight loss.Level of evidence: IIStrength of recommendation: AMost NAFLD patients fail to meet current recommendations for physical activity. Daily physical activity should be measured in each patient and counselling for exercise should be provided.Training improves cardio-respiratory fitness, insulin resistance and liver enzymes, independent of weight loss. Any increase in physical activity over baseline or even avoidance of sedentariness is desirable, but vigorous exercising should be avoided in individuals known to be prone to cardiovascular disease.Level of evidence: IIStrength of recommendation: A

6.2. Anti-obesity drugs

Drug therapy of obesity (orlistat and sibutramine) has not shown a direct beneficial effect on the liver independent of thebeneficial effect of weight loss. However, these drugs may enhance the beneficial effects of behavioural therapy. The finding that psychiatric side-effects outweighed the metabolic benefits resulted in the discontinuing of all trials with commercially available CB1 receptors blockers.

Level of evidence: III–IIStrength of recommendation: C

6.3. Bariatric surgery

Although bariatric surgery is not specifically indicated in NAFLD, it may be useful in morbidly obese patients. A metanalytic review has reported improved liver histology following gastric by-pass and LAP-banding. However, a recent Cochrane database systematic review reported that the lack of randomised clinical trials precludes the assessment of benefits and harm of bariatric surgery as a therapeutic approach for patients with NASH .

Level of evidence: IVStrength of recommendation: B–C

6.4. Insulin sensitisersInsulin sensitisers such as metformin and glitazones are associated with normalisation of transaminases in 50% of cases, decreased steatosis (evaluated through ultrasonography and MR spectroscopy), a partial improvement in necro-inflammation and, less evident, in fibrosis in a 1-year follow-up. Longer duration of treatment does not increase the success rate. Liver enzymes will invariably return to pre-treatment values and liver histology will rapidly deteriorate after cessation of treatment. In addition, cardiovascular side-effects have been reported following administration of glitazones. In NAFLD, their use should be restricted to randomised controlled trials in non-responders to standard lifestyle changes.

Level of evidence: II–IIIStrength of recommendation: B

6.5. Lipid lowering agents

Lipid lowering drugs such as fibrates, statins, omega-3s produce a partial improvement in transaminases.

However, they have no advantage over lifestyle changes.

Level of evidence: III–IVStrength of recommendation: C

6.6. Anti-hypertensive agents

Blood pressure control is aimed at reducing cardiovascularrisk and the effects on liver disease are uncertain. However, angiotensin-receptor blockers have favourable metabolic effects, and a pilot study with losartan showed moderate effects on hepatic histology. The use of these drugs should be restricted to NAFLD subjects with arterial hypertensionuntil more evidence will be available.

Level of evidence: IIIStrength of recommendation: C

6.7. Cyto-protective and antioxidant agents

Cyto-protective and antioxidant agents do not have substantial advantages compared with behavioural changes on modification of biochemical parameters. Conflicting data have been reported with UDCA.Level of evidence: II–IIIStrength of recommendation: C

Supplementation with vitamin E and C, which have mainly been tested in paediatric NAFLD, were reported as ineffective on biochemical and histological outcomes. Positive results have been demonstrated for vitamin E in association with UDCA and additional data (the large PIVENS trial of the NASH CRN Research Group), which will soon be released, are eagerly awaited.Level of evidence: IIIStrength of recommendation: C

In summary, the results of this trial of pioglitazone and vitamin E for the treatment of nonalcoholic steatohepatitis in adults without diabetes showed that vitamin E was superior to placeboand suggested that pioglitazone may also have efficacy.

Although only subjects who received vitamin E met the criteria for the prespecified primary outcome measure (an improvement in histologic findings, which required an improvement by 1 or more points in the hepatocellular ballooning score; no increase in the fibrosis score; and either a decrease in the activity score for nonalcoholic fatty liver disease to a score of 3 or less or a decrease in the activity score of at least 2 points, with at least a 1-point decrease in either the lobular inflammation or steatosis score)subjects who received pioglitazone had significant improvement in other important histologic features of nonalcoholic steatohepatitis.

Sanyal NEJM 2010

Un’analisi critica dei trial terapeutici

Following lifestyle intervention, insulin-sensitizing agents (mainly RSG and pioglitazone) and anti-oxidants (betain and vitamin E), no improvement in fibrosis was noted, but only in the grade of steatosis, necro-inflammation, and ballooning at light microscopy.

This might either mirror the inclusion of fibrotic disease, for which reversal could be problematic or fails to show that any of the interventions truly halts the pathogenic cascade triggered by insulin resistance.

Lonardo, Bellentani, Ratziu, Loria Expert Review Gastro Hepatol IN PRESS

Arrese, Hepatology

6.8. Venesection

Particularly in subjects with elevated ferritin levels, or with HFE gene mutations indicative of hereditary haemochromatosis, iron depletion through venesection can be proposed.

Level of evidence: IVStrength of recommendation: B

6.10. Conclusions

In conclusion, owing to the lack of hard data, administration of drug agents or the practice of surgical interventions should be reserved to controlled studies of evolutive NAFLD, unless otherwise motivated by other health requirements.

It is recommended that such therapeutic studies be designedand performed with the aim of providing clinically useful information.

To this end, liver biopsy at entry and second biopsy at scheduled interval should be performed.


7. Follow-up

Natural history data have shown that individuals with uncomplicated nonalcoholic steatosis should be reassured about the benign course of disease.Based on these data it is advisable that patients with steatosis undergo a “low intensity” surveillance schedule. Patients with NASH should be monitored as patients with chronic viral hepatitis.


FEGATO & DIABETE(attenti a quei 2 !)

Genetics, lifestyle, weight gain

INITIAL INSULIN RESISTANCE

Fetuin-A, Protein kinase C, Liver Fibrosis, IL-6

Pancreatic ß cell lipotoxicity

Type 2 Diabetes Mellitus

Fatty liver

PROTRACTED INSULIN RESISTANCE

Type 2 Diabetes Mellitus

Iron overload,Insulin resistance,SteatosisPTEN,Apoptosis of hepatocytesOxidative stress Adipokine/cytokine DNA damage

NASHFibrosisCirrhosisHCC

H

E

P

A

T

C

Y

T

E

Liver-related death

7.2. Metabolic and cardiovascular riskGiven these patients’ increased risk of developing diabetes and MS, laboratory parameters exploring common metabolic disorders should be repeated at timed intervals (6–12 months).The interval between check-ups should keep into account the severity of liver disease and the metabolic risk in the individual patient.Based on the evidence of early atherosclerosis andincreased cardiovascular mortality particularly in the 45–54 year age group, NASH patients should undergo periodic noninvasive evaluation of their cardiovascular risk.


L’asse fegato-vasi

Loria-Lonardo-Targher Clinical Science 2008;115, 1–12

Expanded and inflamed abdominal adipose tissue

Inflammatory cytokinesInsulin resistance

NEFAInflammatory cytokinesInsulin resistance

Oxidative stressInflammationLipotixicity

NASHPure steatosis

C reactive proteinFibrinogenPlasminogen activator inhibitor-1Oxidative stressTriacylglycerol-rich VLDL, small dense LDL

HDL2

Postprandial lipaemiaGlucose dysregulationInsulin resistance

Atherosclerosis

Meccanismi attraverso i quali il fegato grasso è pro-aterogeno

Targher & Day NEJM 2010

7.3. Risk of cancer

Similar to those with obesity and diabetes, hospitalisedindividuals with fatty liver have been reported to be atincreased risk for some extra-hepatic cancers and cancer wasthe first cause of death in a population based cohort study. Based on the above studies, generalised cancer screening programs cannot be proposed to all NAFLD patients. However, tailored screening strategies may be discussed on an individual basis on the grounds of familial and personal risk of cancer and on patient’s informed consent.Level of evidence: V–VIStrength of recommendation: B–C

8. Prevention

No specific studies about NAFLD prevention are available. However, given the association of NAFLD with poor physical fitness and diets rich in soft drinks, fructose, carbohydrates and saturated fatty acids it is reasonable to speculate that a policy reducing these risk factors may result in a decreased incidence of NAFLD in cohorts at high risk.

Level of evidence: VIStrength of recommendation: A

9. NAFLD and orthotopic liver transplantation (OLT)

Steatosis <30% in the donor’s liver does not

affect the success rate of the transplant.

Steatosis risk factors that are present pre-OLT

in the recipient will often worsen after OLT.


Strength of recommendation: B

10. Research agenda

Based on the present document, the Expert Committee recommends priority for the following research items:

• Epidemiology: Multi-centre prospective long-term (≥20 years) follow-up studies. Genetic characterisation, particularly in subjects with no risk factors.

• NAFLD, HCV and the metabolic syndrome: Impact of “metabolic” therapeutic strategies associated with virologic schedules. Study of the host’s genetic features.

• Clinical manifestations: Registry of cryptogenic cirrhosis; characterisation of non-insulin-resistant cases of NAFLD or insulinresistant NAFLD without risk factors.

• Diagnosis: Sample variability of liver biopsy. Genetic and endocrine determinants of progressive disease.

• Treatment: Controlled large-scale studies with histological endpoints.• Follow-up: Study of non-invasive predictors of early cirrhosis (e.g., scores,

laboratory and imaging, transient elastography). Assessment of cancer risk: affected organs and assessment of risk rate.

• Prevention: Effectiveness of prevention strategies, particularly in children, teen-agers and young adults.

• OLT: Steatosic liver as marginal graft. Recurrence of NASH in the post-transplant setting.

CONCLUSIONI

Abbiamo presentato le linee guida italiane sulla NAFLD.

Difficoltà derivano dal fatto che la patologia è asintomatica, il consumo di alcol è self-reported, e la diagnosi richiede la biopsia.

Ci siamo pertanto soffermati su:• storia naturale della malattia• indicazioni ad ecografia e biopsia epatiche• rapporti tra fegato e diabete• gestione “globale” del paziente con NAFLD che tenga conto di rischi

di tipo epatologico, metabolico e vascolare.

Confermato il ruolo di misure volte a migliorare le abitudini di vita del paziente. Terapie farmacologiche o di chirurgia bariatrica sono confinate a studi clinici.

Hepatology. 2011 Jun;53(6):1883-94. doi: 10.1002/hep.24283. Epub 2011 May 14. Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease. Sookoian S, Pirola CJ.

Our objective was to estimate the strength of the effect of the I148M (rs738409 C/G) patatin-like phospholipase domain containing 3 (PNPLA3) variant on nonalcoholic fatty liver (NAFLD) and disease severity across different populations. We performed a systematic review by a meta-analysis; literature searches identified 16 studies. Our results showed that rs738409 exerted a strong influence not only on liver fat accumulation (GG homozygous showed 73% higher lipid fat content when compared with CC ones, data from 2,937 subjects; P < 1 × 10(-9) ), but also on the susceptibility of a more aggressive disease (GG homozygous had 3.24-fold greater risk of higher necroinflammatory scores and 3.2-fold greater risk of developing fibrosis when compared with CC homozygous; P < 1 × 10(-9) ; data from 1,739 and 2,251 individuals, respectively). Nonalcoholic steatohepatitis (NASH) was more frequently observed in GG than CC homozygous (odds ratio [OR] 3.488, 95% confidence interval [CI] 1.859-6.545, random model; P < 2 × 10(-4) ; data from 2,124 patients). Evaluation of the risk associated with heterozygosity for the variant suggests that the additive genetic model best explains the effect of rs738409 on the susceptibility to develop NAFLD. Nevertheless, carrying two G alleles does not seem to increase the risk of severe histological features. Meta-regression showed a negative correlation between male sex and the effect of rs738409 on liver fat content (slope: -2.45 ± 1.04; P < 0.02). The rs738409 GG genotype versus the CC genotype was associated with a 28% increase in serum alanine aminotransferase levels. CONCLUSION: By summarizing the amount of evidence, this study provided unequivocal evidence of rs738409 as a strong modifier of the natural history of NAFLD in different populations around the world.

Revisione &

discussione

domande a scelta multipla

Domanda 1

L’EPATOPATIA PIU’ FREQUENTE IN ITALIA

• Epatite cronica da HCV

• Epatite acuta da HBV

• Steatosi epatica

• Epatopatia alcolica

• Morbo di Wilson

Domanda 2

RAPPORTI TRA FEGATO E DIABETE• I diabetici tipo 2 sono protetti da malattie epatiche, in

particolare la cirrosi in quanto muoiono prima di altre cause, tipicamente vascolari, uremia e infezioni

• Le epatopatie sono una delle prime cause di morte nel diabetico tipo 2

• Il fegato grasso può anticipare lo sviluppo del diabete tipo 2 o esserne la conseguenza

• Il diabete tipo 2 è un fattore di rischio di insorgenza di epatocarcinoma

• Sono vere le risposte b), c), d)

Domanda 3

QUALE DELLE SEGUENTI AFFERMAZIONI E’ FALSA• Un soggetto con steatosi non alcolica non può presentare

anche un’epatopatia di causa diversa (ad esempio alcolica o da HCV)

• L’infezione da HCV è di per sé diabetogena• La cirrosi, indipendentemente dalla sua eziologia, è

diabetogena• Nel diabete di tipo 2 di nuova insorgenza è indicata la

ricerca di HCV se il paziente è magro• HCV si associa a steatosi epatica in percentuale superiore

all’attesa per la coincidenza casuale delle due malattie

Domanda 4

CONDOTTA DA IN PAZIENTE ASINTOMATICO AL PRIMO RISCONTRO DI TRANSAMINASI ALTERATE

• Inviare allo specialista

• Fare Ecografia epatica

• Ricerco l’HCV

• Controllo la ferritinemia

• Ripeto le transaminasi dopo un mese

Domanda 5

CONDOTTA DA TENERE IN PAZIENTE ASINTOMATICO CON TRANSAMINASI PERSISTENTEMENTE ALTERATE

• Devo dirgli di smettere di bere

• Lo metto a dieta

• Lo propongo per biopsia epatica

• Gli faccio una colangio RM

• Integro consigli igienico-comportamentali con indagini ulteriori non invasive