Terapia della NAFLD/NASH
F. Angelico
Dottorato in Epatologia Sperimentale e Clinica
Attuali conoscenze

La NAFLD è una condizione molto comune con
una prevalenza in continuo aumento.

La NAFLD è una causa indipendente di aumento
di mortalità.

Non esiste alcuna terapia efficace per la NAFLD
La malattia comprende un ampio spettro di danno
epatico che va dalla semplice steatosi alla steatoepatite, alla fibrosi di vario grado, alla cirrosi e
all’epatocarcinoma.
Il quadro istologico simile al danno alcolico in
assenza di abuso alcolico (<20gr/die)
Proposed Histologic Spectrum NAFLD
Fat
+
Inflammation
Fat
Inflammation
Ballooning
Degeneration
Fat
Ballooning
Degeneration
Fibrosis
+/-Mallory Bodies
Stage IV
Stage III
Stage II
FAT
Stage I
Matteoni et al, Gastroenterol 1999
What are the settings for NAFLD
obesity
50%
steatosis
33%
metabolic disorders
steatohepatitis
50%
fibrosis
T2DM
CVD, malignancy
15%~30%
cirrhosis
30%~40%
liver-related morbidity and mortality
Patrick L. Altern Med Rev, 2002, 7:276-291
NAFLD: Prevalence Data
Obesity
60-95%
Metabolic Syndrome
“Syndrome of Insulin Resistance”
Steatosis
NASH
Visceral
Obesity
NIDDM
TG
HDL
Hypertension
Potential Pharmacologic Treatment
Options for NALFD
Insulin Sensitizing Agents
 Troglitazone/Rosiglitazone
 Metformin
Lipid-Lowering Agents
 Clofibrate, Gemfibrozil
 Statins, Ezetimibe
Membrane-Stabilizing
 Ursodeoxycholic Acid
 Betaine ( SAMe)
Anti-Oxidants


Future Potential Treatments
 Antifibrotics
 Probiotics
 Silymarin, SAMe




Vitamin E
Lecithin
Vitamin C
B-Carotene
Selenium
Vitamin B Complex
Principali risultati. Solo 3 trials clinici randomizzati sono
stati inclusi nell’analisi. Nessuno era in cieco. In due trials la
metformina si associava ad una significativa riduzione delle
transaminasi e del quadro ecografico rispetto alla dieta e al
trattamento con vitamina E. Nell’unico studio effettuato con il
pioglitazione si osservava un miglioramento significativo
dell’istologia del fegato.
Conclusioni. Al momento non ci sono sufficienti
informazioni a favore o contro l’impiego dei farmaci insulinosensibilizzanti nei pazienti con NAFLD/NASH.
Metformina verso controllo
outcome: normalizzazione delle transaminasi
MAIN RESULTS We identified six trials: two of high and four of
low methodological quality. Treatment with antioxidant supplements
showed a significant, though not clinically relevant, amelioration of
transaminases, as compared to placebo or other interventions.
Gamma-GT was decreased, albeit not significantly, in the treatment
arm. Radiological and histological data were too limited to draw any
definite conclusions on the effectiveness of these agents.
CONCLUSIONS There is insufficient data to either support or
refute the use of antioxidant supplements for patients with NAFLD.
Probiotics for non-alcoholic fatty liver disease
and/or steatohepatitis
Lirussi F, Mastropasqua E, Orando S, Orlando R.
Bile acids for non-alcoholic fatty liver disease
and/or steatohepatitis
Orlando R, Azzalini L, Orando S, Lirussi F.
Cochrane Database Syst Rev. 2007 Jan 24;(1):CD005160
STATINE e NAFLD/NASH
EZETIMIBE
Forty-nine RCTs (30 in NASH) were included: 23 RCTs had
post-treatment histology. Most RCTs were small and did not
exceed 1-year duration.
Weight loss was safe and dose-dependently improved histology in
NASH, but more than 50% of patients failed to achieve target
weight loss.
Thiazolidinediones improved steatosis and inflammation but
yielded significant weight gain.
Antioxidants yielded conflicting results and were heterogeneous
with respect to type and dose of drug.
Polyunsaturated fatty acid (PUFA) ameliorated biochemical and
radiological markers of NAFLD.
Conclusion: Well-designed RCTs of adequate size
and duration, with histological endpoints, are
needed to assess long-term safety and efficacy
of proposed treatments on patient-oriented
clinical outcomes.
NAFLD
FATTORE DI RISCHIO
CARDIOVASCOLARE
EPATICO
Sindrome metabolica
Steato-epatite
Diabete tipo 2
Dislipidemia aterogena
Ipertensione
Fibrosi
Arteriosclerosi
Cirrosi
Mortalità
cardiovascolare
Mortalità
epatica
Patogenesi della NAFLD/NASH
Teoria dei “2 Hit”
“First hit” – Eccesso di accumulo di grasso
“Second hit” – Stress ossidativo intraepatico
Perossidazione lipidica
TNF-alpha, citochine infiammatorie
Two-hit hypothesis


Day & James 1985
First hit: macrovesicular steatosis
* Insulin resistance
* Peroxisome proliferatorsactivated receptor (PPAR)
Sencond hit: oxidative stress
* tumor necrosis factor
(TNF – α)
Day CP, James OF. Gastroenterolgy 1998; 114: 842-5.
I hit:
Dal fegato normale al fegato grasso
II hit: dalla steatosi alla steato-epatite
NAFLD
FATTORE DI RISCHIO
CARDIOVASCOLARE
EPATICO
Sindrome metabolica
Steato-epatite
Diabete tipo 2
Dislipidemia aterogena
Ipertensione
Fibrosi
Arteriosclerosi
Cirrosi
Mortalità
cardiovascolare
Mortalità
epatica
The cardiovascular morbidity and mortality is
perhaps one of the most important aspects of
NAFLD and NASH, and our knowledge of their
association is evolving rapidly.
The patients with NAFLD have very high
prevalence of cardiovascular risk factors and
atherosclerosis and high incidence of
cardiovascular morbidity and mortality.
Recently it has been suggested that NAFLD poses
cardiovascular risk above and beyond that is
conferred by the presence of the metabolic
syndrome.
Several longitudinal studies have shown that
cardiovascular disease is much more common than
liver disease as a cause of death in patients with
NAFLD.
Many patients with more severe forms of nonalcoholic fatty liver disease will have major
cardiovascular events and will ultimately die
from cardiovascular disease before advanced
liver disease develops.
The current body of evidence argues for careful
monitoring and evaluation of the risk of
cardiovascular disease in all patients with nonalcoholic fatty liver disease.
Such patients, especially those with nonalcoholic
steatohepatitis, are candidates not only for early
treatment of their liver disease but also for early
and aggressive treatment aimed at their associated
cardiovascular risk factors.