Fatty Liver

Perlemakan hati 14 APRIL 2011

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

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 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

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,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

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 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

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 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

Other drugs

• Betaine• Losartan• Pentoxifylline• Orlistat

Terima Kasih Syukron…