Fatty Liver

Definisi
Pembesaran hati ringan sampai
sedang akibat timbunan difus lemak
netral (trigliserida) dalam
hepatocyte,karena:
a. Peningkatan jumlah asam lemak yang
mencapai hati baik melalui darah
ataupun limfatik
b. Peningkatan sintesis atau penurunan
oksidasi lemak dalam hati
c. Penurunan transpostasi VLDL

Etiologi
Peningkatan influks lemak yang
dimobilisasi dari jaringan adiposa karena
obat,misal: etanol,glukokortikoid
Akibat sekunder dari ketosis diabetes
Peningkatan kadar asam lemak
Penurunan sintesis apoprotein,karena:
a. Kwashiorkor
b. Akibat toksin,seperti
karbontetraklorida,fosfor,etionin
c. Kelebihan dosis tetrasiklin

Patogenesis
Perjalanan Penyakit

Klasifikasi
A. Berdasarkan Penyebabnya
1. Alkoholik
2. Non Alkoholik
B. Berdasarkan Butiran Lemak dalam
Hepatocyte
1. Makrovesikel
2. Mikrovesikel
Alcoholic Fatty Liver
Steatosis atau Perlemakan
hati,hepatosit teregang oleh
vakuola lunak dalam
sitoplasmamakrovesikelinti
hepatosit ke membran sel
Etiologi (Alkoholic Fatty Liver)
a. Kombinasi gangguan oksidasi asam
lemak
b. Peningkatan masukan dan
esterifikasi asam lemak untuk
membentuk triglyserida
c. Menurunnya biosintesis dan sekresi
lipoprotein
Klasifikasi Berdasarkan Butiran Asam Lemak

NONALCOHOLIC FATTY LIVER
DISEASE (NAFLD),
HEPATIC STEATOSIS
(FATTY LIVER), AND
NONALCOHOLIC
STEATOHEPATITIS (NASH)
Defining NAFLD
A liver biopsy showing moderate to gross
macrovesicular fatty change with or without
inflammation (lobular or portal), Mallory bodies,
fibrosis, or cirrhosis.
Negligible alcohol consumption (less than 40 g of
ethanol per week)
History obtained by three physicians
independently.
Random blood assays for ethanol should be
negative.
If performed, desialylated transferrin in serum
should also be negative.
Absence of serologic evidence of hepatitis B or
hepatitis C.
NAFLDSpectrum of
Disease

Simple Steatosis


Steatohepatitis (NASH)


NASH with Fibrosis


Cirrhosis
NAFLD
NAFLDWhy Study it?

Prevalence of NAFLD 13-18% and that of
NASH specifically 2-3%

Is the leading cause of cryptogenic
cirrhosis

Is a disease of all sexes, ethnicities, and
age groups (peak 40-59)

Occurs more frequently in females (65 to
83%)
NASHRisk Factors
0 10 20 30 40 50 60 70
Prevalence (%)
Obesity
High TG
Diabetes
69 to 100
34 to 75
20 to 80
NAFLDRisk Factors
Acquired Metabolic
Disorders
in 38%
*Obesity*
*Diabetes Mellitus*
*Hypertriglyceridemia*
Total Parenteral Nutrition ,Rapid
weight loss, Acute starvation
Surgery
Jejunoileal Bypass
Extensive Small Bowel Loss
Medications
Corticosteroids; Estrogens
Amiodarone
Methotrexate; Tamoxifen
Diltiazem; Nifedipine
Occupational Exposures
Others
Organic Solvents
Wilson's dis,Abetalipoproteinemia
Jejunal diverticulosis
Insulin
resistance
Fatty acids
Steatosis
Lipid
peroxidation
NASH
NAFLDPathogenesis
First Hit
Second Hit
Hepatic iron, leptin,
anti-oxidant deficiencies,
and intestinal bacteria

NAFLDPathogenesis
Triglyceride Accumulation

Insulin Resistance

Lipid Peroxidation and Hepatic Lipotoxicity

Cytokine Activation and Fibrosis

Adiponectin and Leptin (Adipocytokines)

Abnormal Lipoprotein Metabolism
TRIGLYCERIDE ACCUMULATION
1. The normal liver contains less than 5% lipid by weight
2. Excessive importation of FFA
Obesity
Rapid weight loss ,excessive
conversion of carbohydrates and proteins to
triglycerides
3. Impaired VLDL synthesis and secretion
Abetalipoproteinemia,
Protein malnutrition,
Choline deficiency
4. Impaired beta-oxidation of FFA to ATP
Vitamin B5 deficiency,
Coenzyme A deficiency
INSULIN RESISTANCE
Increased
1. Peripheral lipolysis

2. Triglyceride synthesis

3. Hepatic uptake of fatty acids
Lipid Peroxidation & Hepatic
Lipotoxicity
Free radicals defects in mitochondrial oxidative
phosphorylation.

Free radical attack on unsaturated fatty acids

The products of the reaction are another free
radical and a lipid hydroperoxideforms a
second free radical and, amplifies the process.

Imbalance between pro- and antioxidant
substances (oxidative stress)
Cytokine Activation and
Fibrosis
Lipoperoxide induce expression of
inflammatory cytokines

Cytokine level elevation, especially TNF-
has been well described in NAFLD.
Predictors of More Severe
Histology in NASH
Age >4050 y
Female gender
Degree of Obesity or steatosis
Hypertension
Diabetes or insulin resistance
Hypertriglyceridemia
Glucose intolerance
Elevated ALT,AST, -GT level
AST:ALT transaminase ratio >1
Elevated immunoglobulin A level
DIAGNOSE
NAFLDSymptoms
0 10 20 30 40 50 60 70
Prevalence (%)
Asymptomatic
Fatigue
RUQ pain
Edema
Pruritus
GI bleeding
Ascites
NAFLDExam Findings
0 5 10 15 20 25 30 35 40
Prevalence (%)
Normal
Hepatomegaly
Edema
Jaundice
Splenomegaly
Ascites
NAFLDLaboratory
Findings
The AST/ALT ratio is usually less than 1(90%)
Antinuclear antibody positive in ~30%
Increased IgA
Abnormal iron indices in 20% to 60%
Elevated PT and low albumin with cirrhosis
Alkaline phosphatase is less frequently elevated
Hyperbilirubinemia is uncommon

Normal labs do not rule out NAFLD
NAFLDImaging
Ultrasound
Difficulty in differentiating fibrosis from fatty infiltration
Increasing of echogenity diffuse shown hyperechoic
and bright liver
Poor detection if the degree of steatosis is less than
20% to 30%
As initial testing in a suspected case and for large
population screening, it is a reliable and economical

Computed Tomography
Sensitivity and specificity of detecting fatty liver

M R I
to distinguish nodules from malignancy or fat infiltration
Current non-invasive modalities are unable to detect NASH
with or without fibrosis
A. Demonstrates a heterogeneous-appearing
echotexture bright liver
B. Relatively hypodense liver compared to the
spleen (liver-to-spleen ratio <1)
NAFLDHistological
Spectrum
Macrovesicular Steatosis
Lobular Inflammation
Fibrosis
Cirrhosis
T
i
m
e

P
r
o
g
r
e
s
s
i
o
n

Steatosis
>5%10% macrosteatotic hepatocytes
NASH (without fibrosis)
Cirrhosis
(stage 4)
Early stage
3 (bridging
fibrosis)
Classification and Stage
Fibrosis Stages of NASH (Brunt et al. (23))
Stage 1: Zone 3, pericentral vein, sinusoidal or
pericellular fibrosis
Stage 2: Zone 3 sinusoidal fibrosis and zone 1 periportal
fibrosis
Stage 3: Bridging between zone 3 and zone 1
Stage 4: Regenerating nodules, indicating cirrhosis

Types of NAFLD (Matteoni et al. (7))
Type 1: Simple steatosis (no inflammation or fibrosis)
Type 2: Steatosis with lobular inflammation but absent
fibrosis or balloon cells
Type 3: Steatosis, inflammation, and fibrosis of varying
degrees (NASH)
Type 4: Steatosis, inflammation, ballooned cells, and
Mallory hyaline or fibrosis (NASH)

Grading and staging perlemakan
hati non-alkoholik
Grading untuk steatosis
Grade 1 <33% hepatosit terisi lemak
Grade 2 33-66% hepatosit terisi lemak
Grade3 >66% hepatosit terisi lemak
Grading untuk steatohepatis
Grade 1 : Ringan
- Steatosis didominasi makrovesikular, melibatkan
hingga 66% dari lobulus
- Degenerasi balon kadangkala terlihat; di zona 3
hepatosit
- Inflamasi lobular inflamasi akut tersebar dan ringan
(sel PMN), kadangkala inflamasi kronik (sel MN)
- Inflamasi portal tidak ada atau ringan
Grade 2 : sedang
steatosis berbagai derajat, biasanya campuran
makrovesikular dan mikrovesikular
Degenerasi balon jelas terlihat dan terdapat di zona 3
Inflamasi lobular adanya sel PMN dikaitkan dengan
hepatosit yang mengalami degenerasi balon periselular,
inflamasi kronik ringan mungkin ada
Inflamasi portal ringan sampai sedang
Grade 3 : berat
Steatosis meliputi >66% lobulus (panasinar), umumnya
steatosis campuran
Degenerasi balon nyata dan terutama di zona 3
Inflamasi lobular inflamasi akut dan kronik yang
tersebar, sel PMN terkonsentrasi di zona 3 yang
mengalami degenerasi balon dan fibrosis perisinusoidal
Inflamasi portal ringan sampai sedang




Staging untuk fibrosis
Stage 1 fibrosis perivenular zona 3,
perisinusoidal, periselular, ekstensif atau
fokal seperti diatas dengan fibrosis
periportal
Stage 2 yang fokal atau ekstensif
fibrosis jembatan, fokal atau ekstensif
Stage 3 sirosis
Stage 4
Liver biopsy in NASH,
Indications
1. Peripheral stigmata chronic liver
disease

2. Splenomegaly

3. Cytopenia

4. Abnormal iron studies

5. Diabetes and/or significant obesity in
an individual over the age of 45
Insulin
resistance
Fatty acids
Steatosis
Lipid
peroxidation
NASH
Cytoprotectants
Insulin Sensitizers
Antihyperlipidemics
First Hit
Second Hit
Weight Loss
Diet/Exercise
Antioxidants
How to Treat?
Alcoholic Fatty Liver

TREATMENT
Penatalaksanaan NASH
Pengontrolan Faktor resiko
a. Memperbaiki resistensi insulin
b. Mengurangi asupan asam lemak ke
hati
Terapi farmakologis
Pengontrolan Faktor Resiko
1. Mengurangi berat badan dengan diet dan latihan
jasmaniterapi lini pertama
Target Terapikoreksi resistensi insulin & obesitas
sentral
Perbaikan kadar AST/ALT
Caution: penurunan drastis & sindrom yo-yo
memicu progresi penyakit (meningkatnya FA ke
hati shg peroksidasi lemak meningkat)
Treatment:
Latihan aerobik min 30 mnt/hari target denyut nadi
Pengaturan diet
a. mengurangi asupan lemak total mjd < 30% dr total
asupan energi
b. Mengurangi asupan lemak jenuh,diganti dgn
karbohidrat kompleks yg mengandung 15 gr serat
kaya buah & sayur
Weight reduction
Can lead to sustained improvement in
liver enzymes, histology, serum insulin
levels, and quality of life.
Improvement in steatosis following
bariatric surgery
Should not exceed approximately 1.6 kg
per week in adults .

Pengontrolan Faktor Resiko(2)
2.Mengurangi Berat Badan dgn tindakan
bedah (operasi bariatrik)
*apabila gagal dgn pengaturan diet dan
lat.jasmani
*sebagai parameter umum sindrom
metabolik
Target : perbaikan gmbrn histologis
Caution: eksaserbasi steatohepatitis
berpotensi timbul pada penurunan BB
yang mendadak

Terapi Farmakologis
1. Antidiabetik dan Insulin Sensitizer
a. Metforminmeningkatkan krja insulin
pd hepatocyte, menurunkan prod
glukosa hati
Mekanisme : pnghambatan TNF
perbaikan insulin, down regulation
UCP-2 messenger RNA, penurunan
pengikatan DNA pd SREBP-1
Dosis : 3 x 500mg/hari selama 4 bulan
Terapi Farmakologis (2)
(1. Antidiabetik dan Insulin Sensitizer)

b.Tiazolidindion obat antidiabetik
Mekanisme:
i. Memperbaiki sensitivitas insulin pd jar.adiposa
ii. Menghambat ekspresi leptin & TNF
Preparat :
i. Troglizatondtarik dr peredaran, hepatotoksik
ii. Rosiglitazonperbaikan AST,fosfatase alkali, GT,
sensitivitas insulin,fibrosis sentrilobular membaik
iii. Pioglitazonperbaikan aminotranferase dan
derajat steatosis serta nekroinflamasi membaik
Terapi Farmakologis (3)
2. Obat Anti Hiperlipidemia
a. Gemfibrozil perbaikan ALT dan
kadar lipid stlh satu bulan pemberian
b. Statin perbaikan parameter
biokimiawi & histologi pd pasien yg
mendapat atorvastatin
Terapi Farmakologis (4)
3. Antioksidan
mencegah progresi steatosis mjd steatohepatitis dan
fibrosis
a. Vitamin E (a-tokoferol)mghmbt prod sitokin
oleh leukosit
Dosis 300 IU/hari mnurunkan kdr TGF-
b,perbaikan inflamasi dan fibrosis
a. Vitamin C
Dosis vit C 1000 IU/hari dgn kombinasi vit E 1000
IU/hari
a. Betain sbg donor metyl utk pembentukan
lecithyn dlm siklus metabolik metionin
Dosis 20 mg/hari selama 12 bulan
a. N-asetilsisteinantidotum

Terapi Farmakologis (5)
4. Hepatoprotektor
UDCA (Ursodeoxycholic acid) normalisasi enzim
transaminase,stlh pemberian selama 1 tahun
asam empedu dgn byk potensi :
Immunomodulator
Lipid regulation
Cytoprotection
Dosis:
UDCA 13-15 mg/kg/hari selama 1 tahun perbaikan
ALT,fosfatase alkali, GT dan steatosis, namun tidak
ada perbaikan derajat inflamasi dan fibrosis
UDCA 10 mg/kg/hari selama 6 bulan perbaikan tes
faal hati
UDCA 250 mg, 3 x sehari selama 6-12 bulan
perbaikan aminotransferase & petanda fibrogenesis