1. BY: Dr Nahla Azzam GI Fellow III
NASH
BY: Dr Nahla Azzam
GI Fellow III

2. Introduction
NASH Represents a spectrum of conditions characterized histologically by macrovesicular hepatic steatosis in those who do not consume alcohol
It is increasingly recognized cause of liver related mortality and morbidity

3. History of Discovery
It has been ignored till several reports of steatosis and fibrosis in obese patients
It worse following bypass surgery
Ludwig introduce term NASH
Mayo Clinic Proc 1980;55:434

4. Conditions associated with steatohepatitis
1. Alcoholism
2. Insulin resistance
   a. Syndrome X
      i. Obesity
      ii. Diabetes
      iii. Hypertriglyceridemia
      iv. Hypertension
   b. Lipoatrophy
   c. Mauriac syndrome
3. Disorders of lipid metabolism
   a. Abetalipoproteinemia
   b. Hypobetalipoproteinemia
   c. Andersen's disease
   d. Weber-Christian syndrome
4. Total parenteral nutrition

5. 5. Severe weight loss
   a. Jejunoileal bypass
   b. Gastric bypassa
   c. Severe starvation
6. Iatrogenic
   a. Amiodarone
   b. Diltiazem
   c. Tamoxifen
   d. Steroids
   e. Highly active antiretroviral therapy
7. Refeeding syndrome
8. Toxic exposure
   a. Environmental
   b. Workplace

6. Fatty liver found in 10-15% of normal and in 70 % of obese individuals
20% of morbid obese p have NASH
50% of patients with NASH have DM or glucose intolerance

8. Diagnosis 3 criteria : histology of steatohepatitis
Convincing evidence of no alcohol consumption <40 G/W
Negative viral serology

9. . Grading and staging of NAFLD
Grading NAFLD
   1. Macrovesicular steatosis
       Grade 0: None
      Grade 1: Up to 33%
       Grade 2: 33%–66%
       Grade 3: > 66%

10. Grade 1 (mild) Grade 2 (moderate Grade 3 (severe)
Steatosis up to 66%, occasional ballooned hepatocyte (mainly zone 3), scattered intra-acinar neutrophils (PMN)
   Grade 2 (moderate
Steatosis of any degree, obvious zone III ballooning degeneration, intra-acinar PMNs, zone III perisinusoidal fibrosis may be present, mild to moderate, portal and intra-acinar inflammation
   Grade 3 (severe)
Panacinar steatosis, widespread ballooning, intra-acinar inflammation, PMNs associated with ballooned hepatocytes, mild to moderate portal inflammation

11. Staging NAFLD 1. StageI 2. Stage2 3. Stage3 4. Stage4
Zone III perisinusoidal/pericellular fibrosis; focally or extensively present
   2. Stage2
Zone III perisinusoidal/pericellular fibrosis with focal or extensive periportal fibrosis
   3. Stage3
Zone III perisinusoidal/pericellular fibrosis and portal fibrosis with focal or extensive bridging fibrosis
   4. Stage4
Cirrhosis

14. Radiological Exam

16. WHY WE HAVE TO DIAGNOSE NASH

18. Nature History of NASH Limited data about it
Cross sectional study showed that fatty liver rarely progress to NASH
Risk of mortality in NASH not known
NASH without fibrosis have very low risk from death related to liver
hepatology 1995;22:

19. Cont…. 30-40%of NASH have advanced fibrosis at time of diagnosis
↑ mortality among obese ,diabetics
10 p of NASH followed up to 10 y showed 5 year survival was 67% and 10 y survival was 59%
Gastroenterology 1995;108:1607
Gastroenterology 1999;116:

20. MANAGEMENT

21. Weight management

23. Management No RCT on weight reduction
Obese patients with high ALT ,weight reductions of 10% or more was associated with improvement in ALT and ↓hepatomegaly
10% is ideal weight reduction not rapid and not to exceed 1.5kg/w
Gastroentrology 1990;99:1408

25. Exercise utilize fatty acids for oxidation and improve insulin sensitivity
Meta analysis showed that that exercise alone is insufficient to achieve weight loss
Weight loss , exercise and life style modification can have better result
Int J Obes Metab Disord1999;23:S50

26. Pharmacologic therapy
Could be consider for patient with BMI>30
Or with BMI>27 with concomitant risk factor e.g. diabetes
3 drug approved by FDA, phentermine, sibutramine and orlistat.
Value of this drugs to achieve weight reduction has been established
N Eng J Med 2002;346:

27. Phentermine has been tried in RCT in 108 obese women for 36 W
Significant WT loss 13kg in phentermine group versus 4 Kg in placebo
Side effect agitation and insomnia

28. Sibutramine
N J Med 2005;353:

29. sibutramine

30. Rimonabant selecive cannabnoid receptor blocker tried in PCT
Significant WT, ↓ TG , Cholesterol and CVS risk
N Eng J Med 2005;353:

32. Surgical management
Patient with BMI>35 we might consider weight reduction surgery
VBG or Jejunaoileal bypass

36. Bariatric surgery associated with preoperative mortality of 1-2%
Post op complications up to 10%
wound infections PE
Stomal infection
nutrients deficiency

37. Therapy for insulin resistance
2 drugs has been approved to correct insulin resistance (metformin and thiaolidinediones )
metformin was showing improvement in steatosis in animal study
In humans was associated with ALT improvement but no proven data on histology
Lancet 2001;358:
Nat Med 2000;:

38. Pilot study in piglitazone 30 mg /D in 18 p non diabetics with NASH for 48W
72% improvement in ALT
Hisological improvement with p value <0.05
?safety
Hepatology 2004;39 :188

39. Lipid lowering agent
Clofibrate had no benefical effect on LFT or the histology
Gemfibrozil in small controlled trial showed improvement in ALT but not histologt
J Hepato 1999;31:384

40. Drugs protect hepatocytes
UDCA has been tried in 15mg/kg/d in RCT up to 2 years showed no effect over placebo in LFT or histology
Hepatology 2004;39:770

41. Vitamin E in dose of 400IU/D has been tried in 11 children with NASH ,all had improvement in their ALT
J Pediatr 2000;136:734-38

42. Betaine is methionine precursor (hepatoprotective factor)
betaine in 10 p for 1 year showed LFT and histology improvement
In RCT of betaine for 8 W showed 25% improvement in histology
Am J Gastroenterol 2001;96:

43. Cont..
Angiotensin II receptor Antagonist (losartan 50mg) was studied in 8 patients for 48 W
Significant improvement in LFT ,Histology and in 2 patients had disappearance of iron deposition
Hepatology 2004;40:

45. thank you