Fatty Liver
Perlemakan hati 14 APRIL 2011
DefinisiPembesaran hati ringan - sedang(>5% berat hati/5-10% sel lemak dr total hepatosit) 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
Klasifikasi Fatty Liver
A. Berdasarkan Penyebabnya1. Alkoholik2. Non Alkoholik/Hepatitis metabolik/ Hepatitis
Diabetes (Ludwig,1980)
B. Berdasarkan Butiran Lemak dalam Hepatocyte
1. Makrovesikel2. Mikrovesikel
Klasifikasi Berdasarkan Butiran Asam Lemak
Patogenesis
Alcoholic Fatty Liver
Steatosis atau Perlemakan hatihepatosit teregang oleh vakuola lunak dalam sitoplasmamakrovesikelinti hepatosit ke membran sel
Etiologi Peningkatan influks lemak yang
dimobilisasi dari jaringan adiposa karena obat,misal: etanol,glukokortikoid atau akibat sekunder dari ketosis diabetes
Peningkatan kadar asam lemak (sintesis endogen)
Penurunan sintesis apoprotein,karena:a. Kwashiorkorb. Akibat toksin, seperti
karbontetraklorida,fosfor,etioninc. Kelebihan dosis tetrasiklin
Patogenesis(Alcoholic Fatty Liver)
Peningkatan sintesis TG hepatik Penurunan oksidasi asam lemak,
mengakibatkanPeningkatan esterifikasi FA dlm TGfatty liver
Penurunan aktivitas siklus asam sitrat,akibat oksidasi etanol dlm sitosol oleh alcohol dehidrogenaseNADH>>
Oksidasi etanolasetaldehidasetat,mengakibatkan:a. Peningkatan lipogenesis dan sintesis
kholesterol dari asetil Ko-Ab. Hiperlactasidemiapenurunan kapasitas ginjal
untuk ekskresi asam urat
Patogenesis(Alcoholic Fatty Liver)
1. Steatosis tjd krn:a. Pembentukan>>nikotinamide adenin
dinukleotidab. Gang.pbtkn&sekresi lipoproteinc. Pningkatan katabolisme lemak perifer
2. SitokromP450 mengubah obat mjd metabolit toxic
3. Oksidasi etanolradikal bebas4. Alkoholmpengaruhi fungsi
mikrotubulus,mitokondria,fluiditas membran5. Asetaldehidperoksidasi lemak & asetaldehid
protein merusak sitoskeleton dan membran6. Alkoholpningkatan IL-8chemoattractant untuk
neutrofil
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)
Absence of serologic evidence of hepatitis B or hepatitis C.
Is the leading cause of cryptogenic cirrhosis
Perjalanan Penyakit
NAFLD—Spectrum of Disease Simple Steatosis
Steatohepatitis (NASH)
NASH with Fibrosis
Cirrhosis
NAFLD
Predictors of More Severe Histology in NASH
Age >40–50 y Female gender (decrease etanol
metabolism in gaster) Degree of Obesity or steatosis Hypertension Diabetes or insulin resistance Hypertriglyceridemia Glucose intolerance Elevated ALT,AST, γ-GT level AST:ALT transaminase ratio <1 Elevated immunoglobulin A level
NASH—Risk Factors
0 10 20 30 40 50 60 70
Prevalence (%)
Obesity
High TG
Diabetes
69 to 100
34 to 75
20 to 80
NAFLD—Risk Factors
Acquired Metabolic Disorders in 38%
*Obesity**Diabetes Mellitus*
*Hypertriglyceridemia*
Total Parenteral Nutrition ,Rapid weight loss, Acute starvation
SurgeryJejunoileal Bypass
Extensive Small Bowel Loss
Medications
Corticosteroids; Estrogens
Amiodarone
Methotrexate; Tamoxifen
Diltiazem; Nifedipine
Occupational ExposuresOthers
Organic SolventsWilson's dis,Abetalipoproteinemia
Jejunal diverticulosis
Insulin resistance
Fatty acids supply
Steatosis Lipid peroxidation
NASH
NAFLD-Two Hit Theory(Day-James)
First Hit
Second Hit(stress oxidative>>)
Dislipidemia,
DM,Obesity
Insulin resistance,Increasing endotoxin level,uncoupling protein activity,sitocromP450,feritinDecresing antioxidant activity
Stellata cell and proinfammatory cytokine activation
NAFLD—Pathogenesis 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
Increased1. 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-α has been well described in NAFLD.
Adiponectin and Leptin (Adipocytokines) Adoponectin
– A hormone secreted by adipose tissue – Enhance both lipid clearance from plasma
and beta-oxidation of fatty acids in muscle. – Direct anti-inflammatory effects,
Leptin– Coded for by the obesity gene & govern
satiety through action at the hypothalamus– No difference in leptin level was seen
between patients with worsening injury or those without
DIAGNOSE
NAFLD—Symptoms
0 10 20 30 40 50 60 70
Prevalence (%)
Asymptomatic
Fatigue
RUQ pain
Edema
Pruritus
GI bleeding
Ascites
NAFLD—Exam Findings
0 5 10 15 20 25 30 35 40
Prevalence (%)
Normal
Hepatomegaly
Edema
Jaundice
Splenomegaly
Ascites
NAFLD—Laboratory 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
NAFLD—Imaging 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 Ito distinguish nodules from malignancy or fat infiltrationCurrent 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)
Liver biopsy (gold standard) 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
Liver Biopsi Steatosis Imflammatory cell infiltration
(netrofil,mononuclear cell) Hepatocyte ballooning Necrosis Nucleus glycogen Mallory’s Hyalin (smaller) Fibrosis
NAFLD—Histological Spectrum
Macrovesicular Steatosis
Lobular Inflammation
Fibrosis
Cirrhosis
Tim
e
Pro
gre
ssio
n
Steatosis
>5%–10% macrosteatotic hepatocytes
NASH (without fibrosis)
Cirrhosis (stage 4)
Early stage 3 (bridging fibrosis)
Classification and StageFibrosis 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 (Brunt)
Grading untuk steatosisGrade 1 <33% hepatosit terisi lemakGrade 2 33-66% hepatosit terisi lemakGrade3 >66% hepatosit terisi lemak
Grading untuk steatohepatisGrade 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 fibrosisStage 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 sirosisStage 4
TREATMENT
Insulin resistance
Fatty acids
Steatosis
Lipid peroxidation
NASH
Cytoprotectants
Insulin Sensitizers
Antihyperlipidemics
First HitSecond Hit
Weight Loss
Diet/Exercise
Antioxidants
How to Treat?
Fatty Liver
Penatalaksanaan NASH
Pengontrolan Faktor resikoa. Memperbaiki resistensi insulinb. Mengurangi asupan asam lemak ke
hati Terapi farmakologis
Pengontrolan Faktor Resiko1. Mengurangi berat badan dengan diet dan latihan
jasmaniterapi lini pertamaTarget Terapikoreksi resistensi insulin & obesitas sentralPerbaikan kadar AST/ALTCaution: 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 nadiPengaturan 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 metabolikTarget : perbaikan gmbrn histologisCaution: eksaserbasi steatohepatitis berpotensi timbul pada penurunan BB yang mendadak
Terapi Farmakologis1. Antidiabetik dan Insulin Sensitizer
a. Metforminmeningkatkan krja insulin pd hepatocyte, menurunkan prod glukosa hatiMekanisme : pnghambatan TNFα perbaikan insulin, down regulation UCP-2 messenger RNA, penurunan pengikatan DNA pd SREBP-1Dosis : 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.adiposaii. Menghambat ekspresi leptin & TNFα
Preparat :i. Troglizatondtarik dr peredaran, hepatotoksikii. Rosiglitazonperbaikan AST,fosfatase alkali, γ
GT, sensitivitas insulin,fibrosis sentrilobular membaik
iii. Pioglitazonperbaikan aminotranferase dan derajat steatosis serta nekroinflamasi membaik
Terapi Farmakologis (3)
2. Obat Anti Hiperlipidemiaa. Gemfibrozil perbaikan ALT dan
kadar lipid stlh satu bulan pemberianb. Statin perbaikan parameter
biokimiawi & histologi pd pasien yg mendapat atorvastatin
Terapi Farmakologis (4)3. Antioksidan
mencegah progresi steatosis mjd steatohepatitis dan fibrosisa. Vitamin E (a-tokoferol)mghmbt prod sitokin
oleh leukositDosis 300 IU/hari mnurunkan kdr TGF-b,perbaikan inflamasi dan fibrosis
a. Vitamin CDosis vit C 1000 IU/hari dgn kombinasi vit E 1000 IU/hari
a. Betain sbg donor metyl utk pembentukan lecithyn dlm siklus metabolik metioninDosis 20 mg/hari selama 12 bulan
a. N-asetilsisteinantidotum
Terapi Farmakologis (5)4. Hepatoprotektor
UDCA (Ursodeoxycholic acid) normalisasi enzim transaminase,stlh pemberian selama 1 tahunasam empedu dgn byk potensi : Immunomodulator Lipid regulation Cytoprotection Dosis: UDCA 13-15 mg/kg/hari selama 1 tahun perbaikan
ALT,fosfatase alkali, γ 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
Other drugs
Betaine Losartan Pentoxifylline Orlistat