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FATTY LIVER
Dr. Suhaemi, SpPD,finasim

What a real liver looks like

Fatty liver

Normal liver

The Normal attenuation of the liver parenchyma Normal: Liver texture=homogeneous


Assessment of its size , configuration, homogeneity , and contour

Fatty Infiltration

increased sound attenuation =poor definition of posterior aspect of liver ( bright liver)

impaired visualization of borders of hepatic vessels

A. Demonstrates a heterogeneous-appearing echotexture bright liver B. Relatively hypodense liver compared to the spleen (liver-to-spleen ratio <1)

Diffuse Fatty InfiltrationCT

Areas of lower attenuation than normal portal vein/IVC density Hyperdense intrahepatic vessels

Fatty Liver Disease - Definition


A clinico-pathologic syndrome encompassing a wide

range of fatty liver disease in the absence of


significant alcohol intake and other common causes of Steatosis. The following are the stages.
Non Alcoholic Fatty Liver Disease NAFLD

Non Alcoholic Steato Hepatitis NASH


Non Alcoholic Cirrhosis (> 60% of cryptogenic)
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Adipocyte is an Endocrine Organ

The Two HIT Concept

Lipid Accumulation
Oxidative Stress

1st HIT

2nd HIT

Cytokine Activation

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The Two Hit Concept


Diet FFA Fatty Liver Susceptibility Oxidative Stress Toxins Inflammatory Molecules Fats Burnt VLDL-TG

1st Hit

Saturated > Unsaturated

2nd Hit

Apoptosis
Damaged Liver
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Donnelly et al. J. Clin. Invest. 113: 1343, 2005; Day and James. Gastroenterol. 114: 842, 1998

These are a Continuum

Normal
FAT >5%

1st HIT

NASH
Inflammatio n

2nd HIT

Scarring

DCLD

NAFLD

IR and MS

Cirrhosis

IR and MS

CV Risk
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NAFLDHistological Spectrum
Cirrhosis Time Progression

Fibrosis

Lobular Inflammation

Macrovesicular Steatosis

Natural History of Fatty Liver


Simple Steatosis or Fat Deposition of > 5%

Benign course

3% develop cirrhosis

NASH Ballooning, Inflammation, Fibrosis

Worse prognosis

30% develop cirrhosis

Severe NASH with fibrosis 75% go in for cirrhosis

5 yr survival 67%

10 yr survival 45%
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NAFLDPathogenesis

TRIGLYCERIDE ACCUMULATION INSULIN RESISTANCE Lipid Peroxidation and Hepatic Lipotoxicity Cytokine Activation and Fibrosis

Adiponectin and Leptin (Adipocytokines)


Abnormal Lipoprotein Metabolism

The New Definition of MS


Waist Circum

90 (M), 80 (F)
Triglycerides >150 mg

HDL

<40 (M) < 50 (F)

2 of 5

Dysglycemia

FPG >100 or DM

Hypertension

>130 or 85
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Rx. for any of the above conditions

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Each Perpetuating the Other


NAFLD is the Hepatic component of MS

NAFLD

IR

DM

MS

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What is the implication


These are ONE
IR 98%

If we find one look for the other

NASH DM 70% MS 85%

NAFLD NASH

DM, MS, CVD

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IR
Leptin, IL-6 FFA, PC1 Rad, TNF-

Adiponectin
NEFAs

Obesity, PPAR-
NO

in oxidation in DAG & TAG

PC, KC, SC, LEC

TNF-
ATP

Free radicals Antioxidants

CC P450 A,E1
Glutathione PPAR- ,

Kuffer Cells

NF-B

in oxidative stress

SREBP1a,1c,2

NASH, CV Risk

O2 stress, Inflmma.

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The Risk Factors

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What Causes Fatty Liver ?


Alcohol Obesity, WC T2DM

Wilsonss Disease
-1 Anti-trypsin AI Hepatitis

Triglycerides
Medicines*, TPN

Hepatitis C
Inherited syndromes

* MTX, VA, Acetaminophen, TC, Tamoxifen,


Nefidepine, Amiodarone, CCl4
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NAFLDRisk Factors
Acquired Metabolic Disorders *Obesity* Obesity Diabetes *Diabetes Mellitus* Mellitus *Hypertriglyceridemia* Hypertriglyceridemi a Parenteral Nutrition ,Rapid Total weight loss, Acute starvation Jejunoileal Bypass
Extensive Small Bowel Loss

in 38%

Surgery

Corticosteroids; Estrogens Medications


Amiodarone Methotrexate; Tamoxifen

Diltiazem; Nifedipine
Occupational Exposures Others Organic Solvents Wilson's dis,Abetalipoproteinemia Jejunal diverticulosis

Clinical Presentation

Asymptomatic Routine blood tests Liver enzymes Enlarged Liver (1/3) RUQ periumb. Pain Fatigue. Malaise

Anorexia, Nausea > 90% are obese USG e/o fatty liver Acanthosis Nigricans DM, HTN, Lipid abn. OSAS, Snoring
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Laboratory Abnormalities

2 - 4 fold GPT & GOT SGOT: SGPT Ratio <1 AKP slight in 1/3 Dyslipidemia - TG FBG and PPBG BUN & Creatinine N

Normal Albumin. PT Low ANA + < 1 in 320 Serum Ferritin Iron saturation SGOT: SGPT Ratio >1 if Cirrhosis sets in
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How to Treat?
Insulin Sensitizers Antihyperlipidemics Antioxidants Cytoprotectants

First Hit
Insulin resistance Fatty acids

Steatosis

Second Hit
Lipid peroxidation

NASH

Weight Loss Diet/Exercise

Potential Drugs for NAFLD


Insulin Sensitizing Agents

Membrane-Stabilizing

Glitazones; Metformin Clofibrate; Gemfibrozil

Urso deoxy cholic Acid


Betaine (SAM) Vitamin E; Vitamin C Lecithin; Carotene 26

Lipid-Lowering Agents

Anti-Oxidants

Future Potential Treatments

Anti-fibrotics;

Vitamin B Complex

Urso deoxy cholic Acid - UDCA

Evidence of efficacy in NASH/NAFLD is equivocal 300 mg bid or 10 mg/kg in two divided doses PO Given up to 12 to 24 months - depends on response Cholestasis, PBC, PSC, Acute viral hepatitis, HBV, HCV Chronic hepatitis, Alcoholic liver disease Dissolution of cholesterol microliths / gallstones

Class E drug in pregnancy (not to be used in

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There is No Effective Drug Rx.


NAFLD and NASH may resolve with weight loss Liver fat content ; No effect on fibrosis & Inflam. Diet and exercise improve insulin sensitivity, increase oxidative capacity and utilization of FFAs

Weight loss has clear benefits for CV risk & T2DM


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Take Home Points

It is the main cause of liver enzymes; Isnt that benign Spectrum of disease NAFLD NASH Cirrhosis HCC Insulin resistance, MS are the key pathogenic features DM, TG, Non fatty abdominal obesity, increasing age Always look for DM, TG, CVD if you see fatty liver Presently, the management is to improve IR, TG, DM
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