1. Fatty Liver Disease - Definition
Fatty Liver - NAFLD - NASH - CV Risk
21-Jun-09
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)
Dr. R.V.S.N.Sarma., M.D., M.Sc., (Canada)

2. Adipocyte is an Endocrine Organ
Inflammation
Insulin Resistance
NAFLD

3. The Two HIT Concept 1st HIT 2nd HIT Lipid Accumulation
Oxidative Stress
Cytokine Activation
1st HIT
2nd HIT

4. The Two Hit Concept 1st Hit Saturated > Unsaturated 2nd Hit
Fatty Liver
Fats Burnt
VLDL-TG
Diet
FFA
Susceptibility
1st Hit
Saturated >
Unsaturated
Oxidative Stress
2nd Hit
Toxins
Inflammatory
Molecules
Damaged Liver
Apoptosis
Donnelly et al. J. Clin. Invest. 113: 1343, 2005; Day and James. Gastroenterol. 114: 842, 1998

5. These are a Continuum  CV Risk 1st HIT 2nd HIT IR and MS IR and MS
Normal
NAFLD
NASH
Cirrhosis
1st HIT
2nd HIT
FAT >5%
Inflammation
Scarring
DCLD
IR and MS
 CV Risk
IR and MS

6. 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%

7. The New Definition of MS
Waist Circum  90 (M), 80 (F)
Triglycerides >150 mg
HDL <40 (M) < 50 (F)
Dysglycemia FPG >100 or DM
2 of 5
Hypertension >130 or 85
Rx. for any of the above conditions 7

8. Each Perpetuating the Other
NAFLD IR MS DM
NAFLD is the Hepatic component of MS

9. What is the implication
These are ONE
If we find one –
look for the other
NASH
IR 98%
MS 85%
DM 70%
NAFLD NASH
DM, MS, CVD

10. IR Adiponectin  Obesity, PPAR- PC, KC, SC, LEC Kuffer Cells
 Leptin,
 IL-6
 FFA, PC1
 Rad, TNF-
 NEFAs
 NO
PC, KC, SC, LEC
 TNF-
 ATP
 in  oxidation
 in DAG & TAG
Kuffer Cells
 Free radicals
 Antioxidants
 CC P450 A,E1
 Glutathione
 PPAR- , 
 NF-B
 in oxidative stress
 SREBP1a,1c,2
NASH, CV Risk
O2 stress, Inflmma.

11. The Risk Factors

12. What Causes Fatty Liver ?
Alcohol
Obesity,  WC
T2DM
 Triglycerides
Medicines*, TPN
Wilsons’s Disease
-1 Anti-trypsin 
AI Hepatitis
Hepatitis C
Inherited syndromes
* MTX, VA, Acetaminophen, TC, Tamoxifen,
Nefidepine, Amiodarone, CCl4

13. 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

14. 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

15. Potential Drugs for NAFLD
Insulin Sensitizing Agents
Glitazones; Metformin
Lipid-Lowering Agents
Clofibrate; Gemfibrozil
Future Potential Treatments
Anti-fibrotics; Probiotics
Silymarin; Selenium
Membrane-Stabilizing
Urso deoxy cholic Acid
Betaine (SAM)
Anti-Oxidants
Vitamin E; Vitamin C
Lecithin;  -Carotene
Vitamin B Complex

16. 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)

17. 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

18. 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