NAFLD

Dr Allister J GrantConsultant Hepatologist

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

LEICEST

ER

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

NASH

Steatosis Cirrhosis

NASH- Peri-sinusiodal fibrosis

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

NAFLD DiagnosisRole for Liver Biopsy?

NAFLD DiagnosisRole for Liver Biopsy?

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.

Current Management of |NAFLD and NASH. APT. Younossi Z: 2008

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?

Thank you