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. b. c.

Kwashiorkor Akibat toksin,seperti karbontetraklorida,fosfor,etionin 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.
b.

c.

Kombinasi gangguan oksidasi asam lemak Peningkatan masukan dan esterifikasi asam lemak untuk membentuk triglyserida 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
Diabetes

34 to 75 20 to 80 69 to 100
0 10 20 30 40 50 60 70

High TG

Obesity

Prevalence (%)

NAFLDRisk Factors
*Obesity*
Acquired Metabolic Disorders in 38%
*Diabetes Mellitus* *Hypertriglyceridemia* Total Parenteral Nutrition ,Rapid weight loss, Acute starvation Jejunoileal Bypass Extensive Small Bowel Loss Corticosteroids; Estrogens Amiodarone Methotrexate; Tamoxifen Diltiazem; Nifedipine Occupational Exposures Others Organic Solvents Wilson's dis,Abetalipoproteinemia Jejunal diverticulosis

Surgery

Medications

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

Second Hit First Hit

Insulin resistance
Fatty acids Steatosis Lipid peroxidation NASH

NAFLDPathogenesis

Triglyceride Accumulation Insulin Resistance Lipid Peroxidation and Hepatic Lipotoxicity

Cytokine Activation and Fibrosis

Adiponectin and Leptin (Adipocytokines) Abnormal Lipoprotein Metabolism

TRIGLYCERIDE ACCUMULATION
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
1.

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
Ascites GI bleeding Pruritus Edema RUQ pain Fatigue Asymptomatic
0 10 20 30 40 50 60 70

Prevalence (%)

NAFLDExam Findings
Ascites Splenomegaly Jaundice Edema Hepatomegaly Normal
0 5 10 15 20 25 30 35 40

Prevalence (%)

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

MRI 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
Cirrhosis

Time Progression

Fibrosis

Lobular Inflammation

Macrovesicular Steatosis

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 Splenomegaly

2.

3.
4. 5.

Cytopenia
Abnormal iron studies Diabetes and/or significant obesity in an individual over the age of 45

How to Treat?
Insulin Sensitizers
Antihyperlipidemics Antioxidants Cytoprotectants

First Hit
Insulin resistance

Second Hit
Steatosis Lipid peroxidation
Weight Loss Diet/Exercise

NASH

Fatty acids

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 TGFb,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