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How common is NAFLD?
• The most common cause of abnormal liver function tests in the United States.
• Estimated 30.1 million with NAFLD and 8.6 million with NASH
• Affects 10-24% of the population• 58-74% of the obese population• Affects 2.6% of children• 23-53% of obese children
Age Adjusted Prevalence (%) of Age Adjusted Prevalence (%) of Overweight and Obese Americans Aged 20-74yOverweight and Obese Americans Aged 20-74y
Dallas Heart Study ResultsDallas Heart Study Results
Steatosis = 31%Steatosis = 31%Steatosis = 31%Steatosis = 31%
Liver enzymes NORMAL in most (79%) with steatosisLiver enzymes NORMAL in most (79%) with steatosisLiver enzymes NORMAL in most (79%) with steatosisLiver enzymes NORMAL in most (79%) with steatosis
Liver fat< 5.5%
Liver fat> 5.5%
HealthyHealthy FattyFatty
Mean BMI =29Mean BMI =29
Fatty Liver
• Better detected by abdominal imaging than blood tests
• Common in individuals who are– Overweight/obese– Type 2 diabetic– Dyslipidaemic– Regular alcohol consumers
HispanicsHispanics WhitesWhites BlacksBlacks
45%45%42%42%
24%24%
FLDFLD
24%24%M M
M
F
F F
Hepatic SteatosisGender Disparities in Whites
SteatosisSteatosis
SteatohepatitisSteatohepatitis
CirrhosisCirrhosis
Hepatocellular carcinoma
Hepatocellular carcinoma
Non Alcoholic Fatty Liver Disease (NAFLD)Spectrum of Hepatic Pathology
Non Alcoholic Fatty Liver Disease (NAFLD)Spectrum of Hepatic Pathology
Fatty Liver: Macrovescicular steatosis with nucleus positioning at cell periphery
NASH: Mallory bodies, ballooning degeneration,lobular neutrophil inflammationand perisinusoidal fibrosis
AGA Technical Review on Nonalcoholic Fatty Liver DiseaseGastroenterology 2002;123:1705-1725
NAFLD
Grading NAFLD
1.Macrovescicular steatosis
Grade 0: NoneGrade 1: Up to 33%Grade 2: 33%-66%Grade 3: >66%
2. Necroinflammatory activity
Mild, Mod, Severe
Grading and Staging of NAFLDBrunt et al Am J Gastro 1999
Role for Liver Biopsy?Role for Liver Biopsy?
• Confirmatory test
Resolves diagnostic confusionResolves diagnostic confusion(e.g. AIH, HH)(e.g. AIH, HH)
Refines stagingRefines stagingSensitive for “subclinical” fibrosisSensitive for “subclinical” fibrosisImperfect (sampling error)Imperfect (sampling error)
• Invasive procedure
Significant mortality.Significant mortality.
Diseases associated with Steatohepatitis1.Alcoholism2.Insulin resistance a.Metabolic Syndrome
i.Obesityii.Diabetesiii.Hypertriglyceridemiaiv.Hypertension
b.Lipoatrophy c.Mauriac Syndrome d.PCOS
3.Disorders of lipid metabolism a.Abetalipoproteinemia b.Hypobetalipoproteinemia c.Andersen’s disease d.Weber-Christian syndrome
4.Total parenteral nutrition5. HCV
6.Severe weight loss a.Jejuno-ileal bypass b.Gastric bypass c.Severe starvation7.Iatrogenic a.Amiodarone b.Diltiazem c.Tamoxifen d.Steroids e.HAART f. tetracycline g.glucosamine8.Refeeding syndrome9.Exposure to toxic agents a.Environment b.Workplace – Sb,Th,Ba
NAFLD
• NAFLD is a spectrum of disease which includes Fatty liver disease and NASH, but only NASH is known to progress to cirrhosis.
Fatty Liver
Obese BMI>28Centipetal (apple)Bright liver on USSInsulin ResistanceNormal ALT
NASH
Obese BMI>28Bright liver on USSAbnormal ALTFeatures of metabolic syndrome Dyslipidaemia DM HBP
Cirrhosis
Bright/ small liver on USS + splenomegalyAbnormal ALTThrombocytopeniaObesityPoorly controlled DMPoorly controlled lipidsHypertension
2nd hit
FFA oxidationLipogenesisLipid Export
Hepatic Steatosis
High Fat/CHO DietLack of Exercise
Insulin Insulin ResistanceResistance
White Adipose Tissue
Adipokines- adiponectinCytokines- TNF
IL-6
Oxidative Stress
EndotoxinCytokinesROSToxins
NASHPeroxidation of
hepatocyte membraneCytokine release
Stellate cell activation
2nd Hit
Pathogenesis of NASH
FFA oxidationLipogenesisLipid Export
Hepatic Steatosis
High Fat/CHO DietLack of Exercise Pathogenesis of NASH
CellularFFA
Insulin Insulin ResistanceResistance
IB and NFBactivation
IL6 &TNFα
FFA oxidationLipogenesisLipid Export
Hepatic Steatosis
High Fat/CHO DietLack of Exercise Pathogenesis of NASH
CellularFFA
Insulin Insulin ResistanceResistance
GLUT 4 activity
Reduced glucose entry into cells
FFA oxidationLipogenesisLipid Export
Hepatic Steatosis
High Fat/CHO DietLack of Exercise
Insulin Insulin ResistanceResistance
White Adipose Tissue
Adipokines- adiponectinCytokines- TNF
IL-6
Oxidative Stress
EndotoxinCytokinesROSToxins
NASHPeroxidation of
hepatocyte membraneCytokine release
Stellate cell activation
2nd Hit
Treatment StrategiesIn NASH
Diet &Exercise
OrlistatSibutramineRimonabant
StatinsGemfibrozil
MetforminPioglitazoneRosiglitazone
Diet &Exercise
ProbioticsAntioxidants
Bariatric Surgery
Natural history
• Simple steatosis: relatively benign “liver” prognosis with a risk of developing clinical evidence of cirrhosis over 15–20 years in the order of 1%–2%.
• NASH and fibrosis: risk of progress to cirrhosis between 0% at 5 years to 12% over 8 years.
• Cirrhotic: high risk of developing hepatic decompensation and of dying from a liver-related cause including HCC.
NASHAffects 3.5-5% of the population
The rates of progression to cirrhosis have been estimated at between 5% and 20% over 10 years.
There aren't any non-invasive means of predicting which patients are at risk of progression, and there are no agreed guidelines on how to monitor progression.
Initial Investigation
• Look for risk factors– BMI, DM, HBP, Lipids,FHx, Drugs, Alcohol
• Liver screen– Including Glc/GTT/HbA1c/Lipids/AST– Pl, Alb, INR
• USS– Spleen size, fatty liver, collaterals
Managemant of NASH
• The patient should lose weight and exercise
• Pharmacological treatment of Insulin-resistance
• Treatment of Hyperlipidaemia
• Hepatocyte-Protective treatment
NASH Management
1) All patients should be encouraged to exercise, as there is good evidence that even in the absence of weight loss exercise improves NASH.
Obese PatientsWeight reducing diet (aim for 10%, 1-2lb per week)In patients with BMI>28 with risk factors, or >30 without risk factors, consider treatment with Orlistat.
2) Diabetic PatientsGood diabetic control (HbA1c <6.5%) Metformin Thiazolidinediones (rosiglitazone and pioglitazone)Dietician for re-education.Diabetologist if glucose control is difficult.
NASH Management
3) Patients with Hyperlipidaemia and abnormal LFT’sDyslipidaemia should be aggressively addressedDietician ReviewHypercholesterolaemia -Statins Hypertriglycerideaemia -Fibrate. Lipid Clinic
Avoid Drugs
amiodarone, glucocorticoids, methotrexate, nifedipine, synthetic estrogens, tamoxifenAntioxidants?
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