Fatty Liver

DefinisiPembesaran 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. Kwashiorkorb. Akibat toksin,seperti

karbontetraklorida,fosfor,etioninc. Kelebihan dosis tetrasiklin

Patogenesis

Perjalanan Penyakit

KlasifikasiA. Berdasarkan Penyebabnya

1. Alkoholik2. Non Alkoholik

B. Berdasarkan Butiran Lemak dalam Hepatocyte

1. Makrovesikel2. Mikrovesikel

Alcoholic Fatty LiverSteatosis atau Perlemakan hati,hepatosit teregang oleh vakuola lunak dalam sitoplasmamakrovesikelinti hepatosit ke membran sel

Etiologi (Alkoholic Fatty Liver)a. Kombinasi gangguan oksidasi

asam lemakb. 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.

NAFLD—Spectrum of Disease Simple Steatosis

Steatohepatitis (NASH)

NASH with Fibrosis

Cirrhosis

NAFLD

NAFLD—Why 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%)

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 FactorsAcquired Metabolic Disorders in 38%

*Obesity**Diabetes Mellitus*

*Hypertriglyceridemia*Total Parenteral Nutrition ,Rapid

weight loss, Acute starvation

Surgery Jejunoileal BypassExtensive Small Bowel Loss

Medications

Corticosteroids; EstrogensAmiodarone

Methotrexate; TamoxifenDiltiazem; Nifedipine

Occupational ExposuresOthers

Organic SolventsWilson's dis,Abetalipoproteinemia

Jejunal diverticulosis

Insulin resistance Fatty acids

Steatosis Lipid

peroxidation

NASH

NAFLD—Pathogenesis

First HitSecond Hit

Hepatic iron, leptin, anti-oxidant deficiencies, and intestinal bacteria

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 RESISTANCEIncreased

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-α has been well described in NAFLD.

Predictors of More Severe Histology in NASH

Age >40–50 y Female gender 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

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)

NAFLD—Histological Spectrum

Macrovesicular Steatosis

Lobular Inflammation

Fibrosis

Cirrhosis

Tim

e Pr

ogre

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

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

Liver biopsy in NASH, Indications1. 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

CytoprotectantsInsulin SensitizersAntihyperlipidemics

First Hit Second Hit

Weight LossDiet/Exercise

Antioxidants

How to Treat?

Alcoholic Fatty Liver

TREATMENT

Penatalaksanaan NASH Pengontrolan Faktor resiko

a. 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 & TNFαPreparat :i. Troglizatondtarik dr peredaran, hepatotoksikii. Rosiglitazonperbaikan AST,fosfatase alkali, γ GT,

sensitivitas insulin,fibrosis sentrilobular membaikiii. 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 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