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BY: Dr Nahla Azzam GI Fellow III
NASH BY: Dr Nahla Azzam GI Fellow III
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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
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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
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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
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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
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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
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Diagnosis 3 criteria : histology of steatohepatitis
Convincing evidence of no alcohol consumption <40 G/W Negative viral serology
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. 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%
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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
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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
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Radiological Exam
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WHY WE HAVE TO DIAGNOSE NASH
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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:
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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:
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MANAGEMENT
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Weight management
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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
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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
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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:
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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
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Sibutramine N J Med 2005;353:
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sibutramine
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Rimonabant selecive cannabnoid receptor blocker tried in PCT
Significant WT, ↓ TG , Cholesterol and CVS risk N Eng J Med 2005;353:
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Surgical management Patient with BMI>35 we might consider weight reduction surgery VBG or Jejunaoileal bypass
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Bariatric surgery associated with preoperative mortality of 1-2%
Post op complications up to 10% wound infections PE Stomal infection nutrients deficiency
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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;:
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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
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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
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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
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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
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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:
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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:
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thank you
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