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dokumen tentang fatty liver
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Definisi
Pembesaran 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 limfatikb. Peningkatan sintesis atau penurunan oksidasi lemak
dalam hatic. Penurunan transpostasi VLDL
Klasifikasi Fatty Liver
A. Berdasarkan Penyebabnya1. Alkoholik2. Non Alkoholik/Hepatitis metabolik/ Hepatitis
Diabetes (Ludwig,1980)
B. Berdasarkan Butiran Lemak dalam Hepatocyte1. Makrovesikel2. Mikrovesikel
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 toxic3. 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
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,feritin
Decresing 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 ACCUMULATION1. The normal liver contains less than 5% lipid by weight2. Excessive importation of FFA
Obesity Rapid weight loss ,excessive conversion of carbohydrates and proteins to triglycerides
3. Impaired merusakVLDL 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
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 luar biasa
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 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)
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
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
Insulin resistance
Fatty acids
Steatosis
Lipid peroxidation
NASH
Cytoprotectants
Insulin Sensitizers
Antihyperlipidemics
First HitSecond Hit
Weight Loss
Diet/Exercise
Antioxidants
How to Treat?
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 antidiabetikMekanisme: i. Memperbaiki sensitivitas insulin pd jar.adiposaii. Menghambat ekspresi leptin & TNFα
Preparat :iii. Troglizatondtarik dr peredaran, hepatotoksikiv. Rosiglitazonperbaikan AST,fosfatase alkali, γ GT, sensitivitas
insulin,fibrosis sentrilobular membaikv. 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 leukosit
Dosis 300 IU/hari mnurunkan kdr TGF-b,perbaikan inflamasi dan fibrosis
b. Vitamin CDosis vit C 1000 IU/hari dgn kombinasi vit E 1000 IU/hari
c. Betain sbg donor metyl utk pembentukan lecithyn dlm siklus metabolik metioninDosis 20 mg/hari selama 12 bulan
d. 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