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Cause of death 2548 - 2550

Cause %

Cerebrovascular disease Ischemic heart disease HIV / AIDS Transport accident COPD Liver Cirrhosis

11.68.17.76.44.84.3

Normal liver

Fatty liver Genetic and metabolic

Hepatitis or

Steatohepatitis

Fibrosis

Infection

Autoimmune

Chemical

Liver Cirrhosis

Cause of Liver Cirrhosis

• Viral hepatitis

• Alcoholic

• Metabolic

• Cardiac cirrhosis

• Cryptogenic

• NAFLD

Non-alcoholic Fatty Liver Disease

Fatty liver disease (Steatosis)

Fatty liver is excessive accumulation of fat insite the liver cell (Hepatocyte)

Fatty liver disease

• Fatty liver is reversible if the patient stops

drinking, other causes • Fatty liver can lead to steatohepatitis

• Steatohepatitis is fatty liver accompanied by

inflammation• Steatohepatitis can lead scarring of the liver and

developed cirrhosis

Symptoms and Signs

• Usually asymptomatic• Right upper quadrant pain or discomfort• Fatigue or maliase• Symptoms of associated condition• Hepatomegaly with or without tenderness• Signs of chronic liver disease

Diagnosis for NAFLD by noninvasive method

1. Ultrasonography

4 sonographic finding by diffuse fatty change in liver - Diffuse hyperechoice echotexture (Bright liver)

- Increased liver echotexture compared with kidney

- Vascular blurring

- Deep attenuation

2. Computerized tomography

3. Magnetic resonance imaging

Diagnosis for NASH

1. Histologic picture of steatohepatitis

2. Convincing evidence of minimal or no alcohol

consumption (< 40 gm/wk)

3. Absence of serologic evidence of viral hepatitis

Powell et al. Hepatology 1990;11:74-80.

Prevalence of NAFLD

• The most common liver disease in developed

countries • 20 – 40% in western industrial countries • 5 – 30% in Asia – Pacific region • Age 40 – 60 yrs, common in men• Alcohol consumption less than 20 gm/week

Prevalence of NASH

Natural History of NAFLD

Normal

Fatty liver

Steatohepatitis

Steatohepatitis with fibrosis

Cirrhosis ( Fat , Fibrosis)

Natural history of NASH

NASH Cirrhosis Liver related death9 - 20% 30 - 40%

Subacute failure HCC Post OLTxRecurrence

2% 8% ?

Clinical course and prognosis

• Clinically stable disorder • Markedly better prognosis than alcoholic steatohepatitis• NAFLD had slightly lower overall survival than expected

for general population • High mortality was associated with

• advancing age • impaired fasting glucose • cirrhosis

• Important cause of cryptogenic cirrhosis especially in• older • diabetic woman

Causes of fatty liver disease

1. Alcoholic fatty liver disease

2. Non-alcoholic fatty liver disease (NAFLD) • Characterized histologically by mainly

macrovesicular hepatic steatosis • Do not consume alcohol more than 20 gm/week

• NAFLD + Inflammation (NASH) ~ Alcoholic hepatitis• Macrovesicular steatosis • Mallory bodies • Ballooning degeneration• Hepatocyte necrosis • Fibrosis

Conditions Associated With Fatty Liver Disease

1. Alcohol

2. Metabolic Syndrome

3. Disorder of lipid metabolism

4. Total parenteral nutrition

5. Severe weight loss

6. Refeeding syndrome

7. Toxic exposure

8. Iatrogenic • Amiodarone • Diltiazem • Tamoxifen• Steroid • Highly active antiretroviral therapy

Pathophysiology of NASH

Insulin Resistance

Hepatic Steatosis

(Oxidative Stress)

NASH

Diabetes

Inflammatorycytokines

Obesity

Lipid Peroxidation

First step

Second step

Major risk factors for NAFLD

• Central obesity

• Diabetes mellitus type 2

• Dyslipidemia

• Metabolic syndrome

Who is metabolic syndrome?

Three Make The Diagnosis• Abdominal obesity

Men > 40”

Women > 35” • Fasting glucose > 110 mg%• Triglyceride > 150 mg%• HDL

Men < 40 mg%

Women < 50 mg%• Blood pressure : > 130 / > 85 mmHg

Prevention and Treatment

Normal liver

Risk factors

PreventionCauses

Fatty liver Treatment

Prevention

Steatohepatitis Treatment

Liver cirrhosis

Management of Fatty liver disease

1. Prevention• Health promotion

• Prevention of cause

• Controlled associated condition

2. Treatment • No proven effective medical therapy for NAFLD • Modify potential risk factors

• Obesity

• DM

• Hyperlipidemia

• Weight reduction• Gradual weight reduction

• 1.6 kg per week

• Total 10%

• Increase physical activity and diet controlled

Diet for NAFLD

None

Therapy for Co-morbidities

Obesity• Diet with or without exercise

• Bariatric surgery

• Cannabinoid receptor antagonist

Hypertriglyceridemia• Gemfibrozil

• Clofibrate

• Statin

Hypertension• Angiotensin II receptor antagonist

Diabetes• Rosiglitozone

Potential medical treatment for NASH

• Vitamin E and C• Hypoglycemia agent

• Metformin• Pioglitazone• Rosiglitazone

• Probucal• Betaine • Ursodeoxycholic acid • Losartan • Pentoxifylline• Orlistat

Treatment trials for NASH

Trial Treatment n Study type Duration

(mos)

Improved outcome

Anti-oxidant

Lavine

Hasegawa

Harrison

Kugelmas

Vitamin E

Vitamin E

Vitamin E & C

Vitamin E

11

10

45

16

Open label

Open label

RCT

Open label

Varied

6

6

3

ALT, AST, Alkphos

ALT, AST, Markers of fibrosis

Fibrosis (?)

Not different from diet & exercise

ProAnti-oxidant

Abdelmalek Betaine 10 Open label 12 ALT, AST, Histology

Anti-cytokine

Satapathy

Adams

Pentoxifylline

Pentoxifylline

18

20

Open label

Open label

6

12

ALT, AST, TNF, insulin resistance,

steatosis

ALT, AST

Liver Disease : Postgraduate Course 2006.

Author, Year Drug Study

Design

Subject

Number

Duration Hepatic

Steatosis

Neuschwander-Tetri, 2003 Rosiglitazone Open-label 30 48 weeks Improved

Promrat, 2004 Pioglitazone Open-lebel 18 48 weeks Improved

Sanyal, 2004 Pioglitazone

+ Vitamin E

RCT 8 6 months Improved

Belfort, ’06 Diet +/-

Pioglitazone

NCT 55 6 months Improved

Bugianesi, 2005 Metformin RCT 55 6 months Improved

Nair, 2004 Metformin Open-label 15 12 months Limited

improvement

RCT : Randomized Clinical Trial ; NCT : Non-Controlled Trial ; N/A : Not available;

No sig difference : No significant difference

Summary of studies using insulin sensitizers reporting effects upon hepatic steatosis

Summary• Fatty liver disease is the most common liver disease in

developed countries• Fatty liver disease can be lead to liver cirrhosis• The major risk factors are obesity, DM type2, dyslipidemia and metabolic syndrome• No proven effective therapy• Treatment are modify risk factors and weight reduction

•