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NON ALCOHOLIC FATTY

LIVER DISEASE

Dari berbagai sumber Pendidikan


Kedokteran Berkelanjutan
Introduction

Genetik and epigenetic factors

Non-alcoholic
Fatty Liver Disease Non-alcoholic
(NAFLD) Steatohepatitis Cirrhosis HCC
(Simple steatosis) (NASH)
Introduction

NAFLD is the most common liver disorder in


Western countries
affecting 2040% of the general population.
China, Japan, and Korea 12% to 24% in population
subgroups, depending on age, gender, ethnicity,
and location (urban vs. rural).
Metabolic syndrome was associated with
increasing prevalence of NAFLD/NASH
China 5 24% ; India 5 28% ; Indonesia ~
30%
Japan 9 30% ; Malaysia 15 17%
(Hashimoto E. 17th APASL Conference; Kyoto, Japan, 2007)
Table 1. International Diabetes Federation definition of the
metabolic syndrome
Table 2. World Health Organization criteria for defining
the metabolic syndrome in the AsiaPacific region

Diabetes mellitus: fasting


plasma glucose 7.0
mmol/L and/or 2-h plasma
glucose 11.1 mmol/L

Impaired glucose
regulation: by fasting
plasma glucose 6.16.9
mmol/L and/or 2-h plasma
glucose 7.811.1 mmol/L

Insulin resistance: below


lowest quartile of glucose
uptake in the euglycemic
clamp
RISK FACTORS OF NAFLD
Table 3. The risk of fatty liver increases according to the number
of components of metabolic syndrome

(Fan et al.2007. Journal of Gastroenterology and Hepatology 22: 794800)

Table 4 The risk DM progress to NAFLD in obese population of

(Bayupurnama et al., The Internet Journal of Gastroenterology 2010)


Table 5. Clinocopathology feature in obesity+ DM patient
with NAFLD

46 obese patients: 23 subjects as case group (obesity +diabetes mellitus,


and 23 subjects as control group (obesity) (Bayupurnama et al., The
Internet Journal of Gastroenterology 2010)
PATHOGENESIS OF
NAFLD/ NASH
The Multi-Hit Hypothesis of NAFLD/NASH
Genetic factors Environmental Factors
Adipocyte
(polymorphism) (Diet)

Increased of delivery of dietary


Normal liver Lipolisis fat
Increased of mitochondrial
Insulin resistance synthesis of fatty acids or
Hit 1 Fatty acids reduced oxidation
Impaired export of triglyseride
PPAR
out of the liver
Steatosis Excess carbohydrate delivered
Antioxidants to the liver
Oxidative stress
UCP-2

ROS
Lipid peroxidation
Hit 2 Nekrosis
Kemotaksis Cytokine induction
NASH Fibrosis
Mallory bodies
IL-8, IL-10, TNF

Ischemic/LPS Inflamatory
Hit 3 cell
Hepatocyte
PDGF; TGF; IGF
TNF; EGF
Kupffer cell
Endothelial

Cirrhosis cell

Proliferation, migration,
Chemoatractant,Fibrogenesis,
contractility, retinoid loss A-HSC
Q-HSC
DIAGNOSIS NAFLD
Evaluation of suspected
nonalcoholic fatty liver disease
Exclude alcohol use (no more than 12 drinks per day)
Exclude secondary causes of fatty liver:
- Drugs (corticosteroids, amiodarone, methotrexate, CCB,
tamoxifen)
- Altered nutritional states (intestinal bypass surgery, rapid
weight loss, TPN, cachexia)
- Metabolic or genetic causes (Wilson disease, lipodystrophy)
- Miscellaneous (HIV, IBD, bacterial overgrowth,
environmental hepatotoxins)
Exclude other liver diseases such as:
- Hepatitis B and C
- Alpha-1 antitrypsin deficiency
- Hemochromatosis (iron studies)
- Autoimmune hepatitis (anti-smooth muscle antibody,
antinuclear antibody)
- Wilson disease (ceruloplasmin)
Imaging studies to look for hepatic
steatosis:
USG (increased echo)

-
CT (low
attenuation)
Hee C., Younossi ZM. 2 0 0 8.
CLEVELAND CLINIC JOURNAL OF MEDICINE 75(10): 721-728
Liver Biopsy

Histologic classification
1. Fatty liver alone
2. Fatty liver with inflammation
3. Fatty liver with ballooning degeneration
and inflammation of PMN cells
4. Fatty liver with fibrosis and/or Mallory bodies

* No. 3 and 4 are classified as NASH


ading and staging of NAFLD

ading for steatosis


grade 1 : < 33% of hepatocytes affected
grade 2 : 33 66% of hepatocytes
affected
grade 3 : > 66% of hepatocytes affected
PREVENTION &
TREATMENT NAFLD/NASH
NAFLD Treatment

Main goals:
to reduce / reverse fibrosis progression
to prevent hepatic cirrhosis

Limitation:
Lack of positive large scale RCT
Most studies were open-label / pilot
Treatment targets according to the pathogenesis
mechanisms of NAFLD and NASH
NAFLD Treatment:
Lipid-lowering Studies
Angulo et al. 2005

Study Drug No. Design Compar Duration ALT/ AST Histology


Patien ed with of Tx
ts (month)
Laurine, et al. Clofibrat 16 Open Baselin 12 No No
(1996) e label e Improve Improve
ment ment
Basaranoglo, Gemfibr 46 Randomi No 1 Improved Not
et al. (1999) ozil zed treatme Done
(Open nt
Label) Baselin
e
Horlander, et Atorvast 7 Open Baselin Up to 12 No Improved
al (2001) atin label e Improve
ment
Merat, et al. Probuco 30 Randomi Placebo 12 Improve Not Done
(2003) l zed ment
(Double
blind)
NAFLD Treatment:
Insulin sensitizer Studies
Study Drug No. Design Compared Duration of ALT/ AST Histology
Patients with Tx (month)

Cadwell, et al. Troglitazone 10 Open Label Baseline 3-6 Improved Improved


(2001)
Acosta, Pioglitazone 8 Open Label Baseline 2-12 Improved Not Done
et al. (2001)
Marchesini et al Metformin 14 Open Label Baseline 4 Improved Not Done
(2001)

Nair,et al.(2002) Metformin 25 Open Label Baseline 6 Improved Not Done

Neuschwander- Rosiglitazone 25 Open Label Baseline 12 Improved Improved


Tetri,
et al.(2002)
Loguercio, et al Probiotics 10 Open Label Baseline 2 Improved Not Done
(2002)
Sanyal, et al. Pioglitazone + 21 Randomized Baseline; 6 Improved Improved
(2002) Vit E (Open Vitamin E
Label) alone
Promrat, et al. Pioglitazone 9 Open Label Baseline 12 Improved Improved
(2003)

Angulo P. et al. 2005


NAFLD Treatment:
Anti-oxidant Studies
Study Drug No. Design Compare Duration ALT/ AST Histology
Patient d with of Tx
s (month)
Miglio, et Betaine 191 Randomiz Placebo 2 Improved* Not Done
al. + ed
(2000) diethanolamin
+ nicotinamid
Abdelmalek Betaine 8 Pilot Study Baseline 12 Improved Improved
,
et al. (2001)
Gulbahar et N- 11 Pilot Study Baseline 3 Improved Not Done
al (2000) acetylsystein
Levine,et al. Vitamin E 11 Pilot Study Baseline 4 10 Improved Not Done
(2000)
Hasegawa, Vitamin E 22 Pilot Study Baseline; 12 Improved Impoved
et al.(2001) diet
Harrison, et Vitamin E + C 45 Randomiz placebo 6 Non Improved
al ed mentioned
(2003) (double-
blind)

Angulo P et al. 2005


No data on long-term maintenance of positive effects
MECHANISMS OF ACTION
OF UDCA

Changes in the
hydrophobicity index of
the bile acid pool
Protection against cell
death induced by
cytotoxic bile acids
Modulation of the
expression of liver
transporters and enzyme
systems
UDCA-induced
normalization of the
altered cellular
(Roma
localization ofet al.,Clinical Science (2011) 121: 523544)
Mechanisms of apoptotic cell death induced by CDCA, the main bile acid
retained in cholestasis, and its protection by UDCA

(2) The extrinsic


pathway

(1)The intrinsic
(mitochondrial pathway)

(3)Apoptosis
by ER stress
Mechanisms of UDCA-induced HCO3 -rich hypercholeresis
Effects of the administration of UDCA to rodents on the expression of
transporters and enzymes involved in bile acid and bilirubin detoxification
Choleretic and anti-cholestatic mechanisms of the taurine-conjugated
metabolite of UDCA (TUDCA) by modulation of the localization status of
canalicular transporters
Inhibition by UDCA of the exacerbated immunological response
occurring in autoimmune hepatopathies
NAFLD Treatment: UDCA Studies

Study Drug No. Design Compared Duration of ALT/ AST Histology


Patients with Tx (month)

Laurine UDCA 24 Open label Baseline 12 Improved Improved


, et al.
(1996)
Guma, UDCA + diet 24 Randomized Baseline 6 Improved Not Done
et al. (OpenLabel)
(1997)
Ceriani, UDCA + diet 31 Open label Diet alone 6 Improved Not Done
et al Baseline
(1998)

Holoma UDCA 24 Open label Diet alone 6 12 Improved Not Done


n, et al. Baseline
(2000)
Lindor, UDCA 166 RCT Placebo 24 Not improved Similar with
et al. (=Placebo) Placebo
(2004)
Dufour, UDCA + 48 Randomized Placebo 24 Improved Improved
et al. Vit.E
(2006)

Angulo P et al. 2005


Take Home Points
Simple steatosis may
progress to Steatohepatitis
and finnally lead to cirrhosis
and/ or HCC
The Multiple Hits is a
pathogenesis of NAFLD /
NASH
Liver Biopsy is the gold
standar diagnosis of
NAFLD/NASH
Many targets treatment are
studied in NAFLD/NASH, but
still in debated
UDCA is one of treatment
Terima Kasih