NASHNASH

BY: BY: Dr Nahla AzzamDr Nahla Azzam

GI Fellow IIIGI Fellow III

IntroductionIntroduction

NASH Represents a spectrum of NASH Represents a spectrum of conditions characterized histologically by conditions characterized histologically by macrovesicular hepatic steatosis in those macrovesicular hepatic steatosis in those who do not consume alcohol who do not consume alcohol

It is increasingly recognized cause of liver It is increasingly recognized cause of liver related mortality and morbidityrelated mortality and morbidity

History of DiscoveryHistory of Discovery

It has been ignored till several reports of It has been ignored till several reports of steatosis and fibrosis in obese patientssteatosis and fibrosis in obese patients

It worse following bypass surgeryIt worse following bypass surgery Ludwig introduce term NASHLudwig introduce term NASH

Mayo Clinic Proc 1980;55:434Mayo Clinic Proc 1980;55:434

Conditions associated with steatohepatitis

1. Alcoholism1. Alcoholism

2. Insulin resistance2. Insulin resistance

      a. Syndrome Xa. Syndrome X

            i. Obesityi. Obesity

            ii. Diabetesii. Diabetes

            iii. Hypertriglyceridemiaiii. Hypertriglyceridemia

            iv. Hypertensioniv. Hypertension

      b. Lipoatrophyb. Lipoatrophy

      c. Mauriac syndromec. Mauriac syndrome

3. Disorders of lipid metabolism3. Disorders of lipid metabolism

      a. Abetalipoproteinemiaa. Abetalipoproteinemia

      b. Hypobetalipoproteinemiab. Hypobetalipoproteinemia

      c. Andersen's diseasec. Andersen's disease

      d. Weber-Christian syndromed. Weber-Christian syndrome

4. Total parenteral nutrition4. Total parenteral nutrition

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

Fatty liver found in 10-15% of normal and Fatty liver found in 10-15% of normal and in 70 % of obese individualsin 70 % of obese individuals

20% of morbid obese p have NASH20% of morbid obese p have NASH 50% of patients with NASH have DM or 50% of patients with NASH have DM or

glucose intolerance glucose intolerance

DiagnosisDiagnosis

3 criteria :3 criteria : histology of steatohepatitishistology of steatohepatitis Convincing evidence of no alcohol Convincing evidence of no alcohol

consumption <40 G/Wconsumption <40 G/W Negative viral serologyNegative viral serology

. Grading and staging of NAFLD

Grading NAFLDGrading NAFLD

      1. 1. Macrovesicular steatosisMacrovesicular steatosis

              Grade 0: NoneGrade 0: None

            Grade 1: Up to 33%Grade 1: Up to 33%

              Grade 2: 33%–66%Grade 2: 33%–66%

              Grade 3: > 66%Grade 3: > 66%

      Grade 1Grade 1 (mild)(mild)

Steatosis up to 66%, occasional ballooned hepatocyte (mainly zone 3), Steatosis up to 66%, occasional ballooned hepatocyte (mainly zone 3), scattered intra-acinar neutrophils (PMN)scattered intra-acinar neutrophils (PMN)

      Grade 2Grade 2 (moderate(moderate

Steatosis of any degree, obvious zone III ballooning degeneration, intra-Steatosis of any degree, obvious zone III ballooning degeneration, intra-acinar PMNs, zone III perisinusoidal fibrosis may be present, mild to acinar PMNs, zone III perisinusoidal fibrosis may be present, mild to

moderate, portal and intra-acinar inflammationmoderate, portal and intra-acinar inflammation

      Grade 3Grade 3 (severe(severe))

Panacinar steatosis, widespread ballooning, intra-acinar inflammation, PMNs Panacinar steatosis, widespread ballooning, intra-acinar inflammation, PMNs associated with ballooned hepatocytes, mild to moderate portal inflammationassociated with ballooned hepatocytes, mild to moderate portal inflammation

Staging Staging NAFLDNAFLD

      1. StageI1. StageI Zone III perisinusoidal/pericellular fibrosis; focally or extensively presentZone III perisinusoidal/pericellular fibrosis; focally or extensively present

      2. Stage22. Stage2Zone III perisinusoidal/pericellular fibrosis with focal or extensive Zone III perisinusoidal/pericellular fibrosis with focal or extensive

periportal fibrosisperiportal fibrosis

      3. Stage33. Stage3Zone III perisinusoidal/pericellular fibrosis and portal fibrosis with focal or Zone III perisinusoidal/pericellular fibrosis and portal fibrosis with focal or

extensive bridging fibrosisextensive bridging fibrosis

      4. Stage44. Stage4 CirrhosisCirrhosis

Radiological ExamRadiological Exam

WHY WE HAVE TO DIAGNOSE NASHWHY WE HAVE TO DIAGNOSE NASH

Nature History of NASHNature History of NASH

Limited data about itLimited data about it Cross sectional study showed that fatty Cross sectional study showed that fatty

liver rarely progress to NASHliver rarely progress to NASH Risk of mortality in NASH not knownRisk of mortality in NASH not known NASH without fibrosis have very low risk NASH without fibrosis have very low risk

from death related to liverfrom death related to liver

hepatology 1995;22:1714-19hepatology 1995;22:1714-19

Cont….Cont….

30-40%of NASH have advanced fibrosis at 30-40%of NASH have advanced fibrosis at time of diagnosistime of diagnosis

↑ ↑ mortality among obese ,diabeticsmortality among obese ,diabetics 10 p of NASH followed up to 10 y showed 10 p of NASH followed up to 10 y showed

5 year survival was 67% and 10 y survival 5 year survival was 67% and 10 y survival was 59%was 59%

Gastroenterology 1995;108:1607Gastroenterology 1995;108:1607

Gastroenterology 1999;116:1413-19Gastroenterology 1999;116:1413-19

MANAGEMENTMANAGEMENT

Weight managementWeight management

ManagementManagement

No RCT on weight reductionNo RCT on weight reduction Obese patients with high ALT ,weight Obese patients with high ALT ,weight

reductions of 10% or more was associated reductions of 10% or more was associated with improvement in ALT and with improvement in ALT and ↓hepatomegaly ↓hepatomegaly

10% is ideal weight reduction not rapid 10% is ideal weight reduction not rapid and not to exceed 1.5kg/wand not to exceed 1.5kg/w

Gastroentrology 1990;99:1408Gastroentrology 1990;99:1408

Exercise utilize fatty acids for oxidation Exercise utilize fatty acids for oxidation and improve insulin sensitivity and improve insulin sensitivity

Meta analysis showed that that exercise Meta analysis showed that that exercise alone is insufficient to achieve weight loss alone is insufficient to achieve weight loss

Weight loss , exercise and life style Weight loss , exercise and life style modification can have better resultmodification can have better result

Int J Obes Metab Disord1999;23:S50Int J Obes Metab Disord1999;23:S50

Pharmacologic therapyPharmacologic therapy

Could be consider for patient with BMI>30Could be consider for patient with BMI>30 Or with BMI>27 with concomitant risk Or with BMI>27 with concomitant risk

factor e.g. diabetes factor e.g. diabetes 3 drug approved by FDA, phentermine, 3 drug approved by FDA, phentermine,

sibutramine and orlistat.sibutramine and orlistat. Value of this drugs to achieve weight Value of this drugs to achieve weight

reduction has been establishedreduction has been established

N Eng J Med 2002;346:591-602N Eng J Med 2002;346:591-602

Phentermine has been tried in RCT in 108 Phentermine has been tried in RCT in 108 obese women for 36 W obese women for 36 W

Significant WT loss 13kg in phentermine Significant WT loss 13kg in phentermine group versus 4 Kg in placebogroup versus 4 Kg in placebo

Side effect agitation and insomnia Side effect agitation and insomnia

SibutramineSibutramine

N J Med 2005;353:2111-20N J Med 2005;353:2111-20

sibutraminesibutramine

Rimonabant selecive cannabnoid receptor Rimonabant selecive cannabnoid receptor blocker tried in PCTblocker tried in PCT

Significant WT, ↓ TG , Cholesterol and Significant WT, ↓ TG , Cholesterol and CVS riskCVS risk

N Eng J Med 2005;353:2121-34N Eng J Med 2005;353:2121-34

Surgical managementSurgical management

Patient with BMI>35 we might consider Patient with BMI>35 we might consider weight reduction surgeryweight reduction surgery

VBG or Jejunaoileal bypass VBG or Jejunaoileal bypass

Bariatric surgery associated with Bariatric surgery associated with preoperative mortality of 1-2%preoperative mortality of 1-2%

Post op complications up to 10%Post op complications up to 10%

wound infectionswound infections

PEPE

Stomal infectionStomal infection

nutrients deficiency nutrients deficiency

TherapyTherapy for insulin resistancefor insulin resistance

2 drugs has been approved to correct insulin 2 drugs has been approved to correct insulin resistance (metformin and thiaolidinediones )resistance (metformin and thiaolidinediones )

metformin was showing improvement in metformin was showing improvement in steatosis in animal studysteatosis in animal study

In humans was associated with ALT In humans was associated with ALT improvement but no proven data on histologyimprovement but no proven data on histology

Lancet 2001;358:893-894Lancet 2001;358:893-894

Nat Med 2000;:998-1003Nat Med 2000;:998-1003

Pilot study in piglitazone 30 mg /D in 18 p Pilot study in piglitazone 30 mg /D in 18 p non diabetics with NASH for 48Wnon diabetics with NASH for 48W

72% improvement in ALT72% improvement in ALT Hisological improvement with p value Hisological improvement with p value

<0.05<0.05 ?safety ?safety

Hepatology 2004;39 :188Hepatology 2004;39 :188

Lipid lowering agentLipid lowering agent

Clofibrate had no benefical effect on LFT Clofibrate had no benefical effect on LFT or the histologyor the histology

Gemfibrozil in small controlled trial showed Gemfibrozil in small controlled trial showed improvement in ALT but not histologtimprovement in ALT but not histologt

J Hepato 1999;31:384J Hepato 1999;31:384

Drugs protect hepatocytesDrugs protect hepatocytes

UDCA has been tried in 15mg/kg/d in RCT UDCA has been tried in 15mg/kg/d in RCT up to 2 years showed no effect over up to 2 years showed no effect over placebo in LFT or histologyplacebo in LFT or histology

Hepatology 2004;39:770Hepatology 2004;39:770

Vitamin E in dose of 400IU/D has been Vitamin E in dose of 400IU/D has been tried in 11 children with NASH ,all had tried in 11 children with NASH ,all had improvement in their ALT improvement in their ALT

J Pediatr 2000;136:734-38J Pediatr 2000;136:734-38

Betaine is methionine precursor Betaine is methionine precursor (hepatoprotective factor)(hepatoprotective factor)

betaine in 10 p for 1 year showed LFT and betaine in 10 p for 1 year showed LFT and histology improvement histology improvement

In RCT of betaine for 8 W showed 25% In RCT of betaine for 8 W showed 25% improvement in histology improvement in histology

Am J Gastroenterol 2001;96:2711-17Am J Gastroenterol 2001;96:2711-17

ContCont....

Angiotensin II receptor Antagonist Angiotensin II receptor Antagonist (losartan 50mg) was studied in 8 patients (losartan 50mg) was studied in 8 patients for 48 Wfor 48 W

Significant improvement in LFT ,Histology Significant improvement in LFT ,Histology and in 2 patients had disappearance of and in 2 patients had disappearance of iron depositioniron deposition

Hepatology 2004;40:1222-25Hepatology 2004;40:1222-25