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
Inflammation
Insulin
Resistance
NAFLD
2
The Two HIT Concept
Lipid Accumulation
1st HIT
Oxidative Stress
2nd HIT
Cytokine Activation
3
The Two Hit Concept
Diet
FFA
Fats Burnt
VLDL-TG
Fatty Liver
Susceptibility
1st Hit
Oxidative Stress
Toxins
Saturated >
Unsaturated
2nd Hit
Inflammatory
Molecules
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
1st HIT
Normal
FAT >5%
Inflammation
NAFLD
IR and MS
2nd HIT
NASH
Scarring
IR and MS
DCLD
Cirrhosis
 CV Risk
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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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The New Definition of MS
Waist Circum
2 of 5
 90 (M), 80 (F)
Triglycerides
>150 mg
HDL
<40 (M) < 50 (F)
Dysglycemia
FPG >100 or DM
Hypertension
>130 or 85
Rx. for any of the above conditions
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7
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
If we find one –
look for the other
IR
98%
NAFLD
NASH
NASH
DM
70%
DM, MS,
CVD
MS
85%
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Adiponectin 
IR
 Leptin,
 IL-6
 FFA, PC1
 Rad, TNF-
Obesity, PPAR-
 NEFAs
PC, KC, SC, LEC
 in  oxidation
 in DAG & TAG
 Free radicals
 Antioxidants
 CC P450 A,E1
 TNF-
 ATP
Kuffer Cells
 Glutathione
 PPAR- , 
 in oxidative
stress
 NO
 NF-B
 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
• Wilsons’s Disease
• Obesity,  WC
• -1 Anti-trypsin 
• T2DM
• AI Hepatitis
•  Triglycerides
• Hepatitis C
• Medicines*, TPN
• Inherited syndromes
* MTX, VA, Acetaminophen, TC, Tamoxifen,
Nefidepine, Amiodarone, CCl4
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Clinical Presentation
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Asymptomatic
Routine blood tests
 Liver enzymes
Enlarged Liver (1/3)
RUQ periumb. Pain
Fatigue. Malaise
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Anorexia, Nausea
> 90% are obese
USG e/o fatty liver
Acanthosis Nigricans
DM, HTN, Lipid abn.
OSAS, Snoring
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Laboratory Abnormalities
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2 - 4 fold  GPT & GOT
SGOT: SGPT Ratio < 1
AKP slight  in 1/3
Dyslipidemia -  TG
FBG and PPBG 
BUN & Creatinine - N
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Normal Albumin. PT
Low ANA + < 1 in 320
 Serum Ferritin
 Iron saturation
SGOT: SGPT Ratio > 1
if Cirrhosis sets in
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Potential Drugs for NAFLD
Insulin Sensitizing Agents
Membrane-Stabilizing
• Glitazones; Metformin
• Urso deoxy cholic Acid
Lipid-Lowering Agents
• Betaine (SAM)
• Clofibrate; Gemfibrozil
Anti-Oxidants
Future Potential Treatments
• Vitamin E; Vitamin C
• Anti-fibrotics; Probiotics • Lecithin; -Carotene
• Silymarin; Selenium
• Vitamin B Complex
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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 COP)
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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; Isn’t 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
• It is a marker of CV Risk. Rx. improve insulin sensitivity
• Modify underlying metabolic risk factors – diet, exercise
• Use Mayo scoring to predict NASH (fibrosis). No biopsy
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