NonNon--Alcoholic Fatty Liver Alcoholic Fatty Liver DiseaseDisease

-- NAFLD NAFLD --

Joel S. Levine, M.D., FACPJoel S. Levine, M.D., FACPProfessor of MedicineProfessor of Medicine

Division of Gastroenterology/HepatologyDivision of Gastroenterology/HepatologyUniversity of Colorado Health Science CenterUniversity of Colorado Health Science Center

Objectives Objectives –– To Understand:To Understand:

• NAFLD – the epidemic and its cause• NAFLD – the clinical spectrum of

disease• NAFLD – diagnostic and therapeutic

decision making

NAFLD: Key points

• Most common liver disorder in U.S.• The hepatic component of the metabolic syndrome• Majority of patients are asymptomatic and do not

get progressive liver disease (NAFL)• At least 20% with associated steatohepatitis

(NASH) develop cirrhosis• The clinical utility of liver biopsy is debated• Evidence-based therapies are lacking

Causes of fatty liver I will not discussMETABOLIC/

NUTRITIONAL DRUGS GENETIC OTHERProtein-calorie malnut. Glucocorticoids Lipodystrophy IBDStarvation Estrogens Weber-Christian Bacterial overgrowthTPN Aspirin Wolmans disease HIV infectionRapid weight loss Calcium channel Fatty liver of PhosphorusWeight reduction blockers pregnancy Petrochemicals

surgery Amiodarone MushroomsTamoxifen Organic solventsTetracyclineMethotrexateValproic acidCocaineAntivirals

Obesity Among U.S. Adults

Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

Body mass indexClassification BMI

Underweight <18.5 kg/m2

Normal weight 18.5-24.9 kg/m2

Overweight 25.9-29.9 kg/m2

Obesity (Class 1) 30-34.9 kg/m2

Obesity (Class 2) 35-39.9 kg/m2

Extreme obesity (Class 3) >40 kg/m2

Sylvester Stallone 5’9” 228 lbs ObeseHarrison Ford 6’1” 218 lbs OverweightGov. Arnold 6’2” 257 lbs ObeseJoel Levine 6’2” 192 lbs Normal (just)Bruce Willis 6’0” 211 lbs OverweightBrad Pitt 6’0” 203 lbs Overweight

Obesity is proposed to be an inflammatory state with theadipocyte now recognized as an endocrine organ that may be responsible for the production of

-inflammation-insulin resistance-NAFLD McCullough, 2002, AASLD

INCREASED FAT MASS(Adipocyte) TNFα

ResistinLeptin

Free fatty acidsAdiponectin

Angiotensinogen

released byadipocytes

FAT MASS(Adipocyte)

FFA

Increased delivery ofFFA to liver

insulin

Peripheral resistanceto insulin’s normal

suppression of lipolysis

- suppression of lipolysis

Adipocytes as endocrine cells

insulin

FIRST HIT:OBESITY

Why is fat harmful to the liver?

• Increased lipid peroxidation and production of large amounts of ROS (increased 10-fold in animal models)

• Increased synthesis of TNFα• Mitochondrial dysfunction

50% reduction in cytochrome c contentrestricted electron flowultrastructural changes200% increase in endogenous H2O2

Normal

Steatosis(fatty liver)

Steatohepatitis

Cirrhosis

Critical transition (2nd hit)

Clinical spectrum of fatty liver disease

25% of adults affectedreversible, few clinical sequelae

Chronic alcohol and obesity are additiveSeldom reverses to normal histologySusceptible to other forms or liver injuryPrecursor to cirrhosis & HCC

Microvesicular steatosis Macrovesicular steatosis

FATTY LIVER – steatosis without inflammation

Dam-Larsen et al GUT 2004;53:750. Danish patients with steatosis but noinflammation. After average follow up of 20 years, only 3% developed significant fibrosis or cirrhosis (as compared to 23% with steatosis related to alcohol)

*NO FIBROSIS = GOOD PROGNOSIS*

NATURAL HISTORY• Patients with simple fatty liver rarely progress, but…• At the time of presentation, 30-40% of patients with

NAFLD have advanced fibrosis and 10-15% have established cirrhosis

• Risk of cirrhosis approaches 20% at 20 years of follow up.

?

2020 gm

Grade 3 (severe) Stage 2-3 fibrosis

NASH

• First described in 1980 by Ludwig

•Associated with fibrosis (15-40%) and cirrhosis (~15%) at the time of diagnosis…

• #1 cause of liver disease in US…

• Increases the susceptibility to other forms of liver injury….

• Accounts for most “cryptogenic” cirrhosis….

• Increases the risk of HCC.

•HOW DO YOU IDENTIFY THOSE AT RISK OF FIBROSIS?

Natural history: Risk factors for fibrotic diseaseAdapted from Angulo et al. Hepatology 1999;30:1356

DIABETES/OBESITYNo Yes

<45

>45

AST/ALT

<1

>1

<1

>1

0

0

12

13

4

50

47

66

Number represents % of patients with NAFLD on imagingstudy who had significant fibrosis on biopsy

AGE

DIAGNOSIS &TREATMENT

A CaseA Case•54 yo healthy WF whose weight increased from 115 to 185 lbs, BMI = 35. Has 2 drinks/week.•At local health fair gets biochemical profile

•AST – 49•ALT – 80•Alkaline Phosphatase – Normal•Total bilirubin – Normal

CaseCase

What are the appropriate

diagnostic tests to perform?

What are the appropriate What are the appropriate diagnostic tests to perform?diagnostic tests to perform?

* Tests for Metabolic Syndrome (BP, Glucose, Lipids) *

Screening for common liver diseasesHCV antibodyHBV surface antigenANATSHFerritin, iron, transferrinHepatic ultrasound

What are the appropriate What are the appropriate diagnostic tests to perform?diagnostic tests to perform?

Screening for uncommon liver diseases

•Alpha-1 antitrypsin (phenotype and level)

•Ceruloplasmin (Wilson disease) – NO !!

•Anti-mitochondrial antibody (AMA) (primary biliary cirrhosis with normal alkaline phosphatase?)

The CaseThe Case

All lab tests normal

Abdominal ultrasound – Fatty Liver

CLINICAL FEATURES

SYMPTOMS - nonspecificasymptomaticfatigueintermittent RUQ fullness

or discomfort

PHYSICAL EXAMINATION - nonspecificobesity in 30-100%hepatomegaly in 50%typical features of cirrhosis

in later stages

LABORATORY ABNORMALITIES - nonspecificincreased aminotransferase activity in 50-90% (<4x)ALT usually greater than ASTGlucose intolerance in 30-50%Hypertriglyceridemia in 20-80%

Pate de Fois Gras Battiste

CaseCase

What now?

Liver Biopsy?

Treatment?

Pate de Fois Gras Battiste

WHEN DO YOU BIOPSY?

Role of a liver biopsy?

• PRO: Only accurate method of staging and diagnosis, convince patient of need for life-style change

• CON: Generally good prognosis, key risk factors can be addressed without a biopsy, lack of effective therapy, cost, risk.

• JSL: Discuss above with patients. Almost none go on to biopsy

Rubens, 1638-1640

Non-alcoholic fatty liver disease(NAFLD) with steatohepatitis

EVALUATION AND MANAGEMENT: THERAPY

There is no established therapy.• Steatosis and steatohepatitis may resolve with weight loss, but the

benefits of a 10% decrease in BMI have been inconsistent• Hepatic fat content decreases, with little effect on fibrosis and

inflammation• Diet and exercise improve insulin sensitivity, increase oxidative

capacity and utilization of fatty acids

• No guidelines have been established, but weight loss has clear benefits for cardiovascular risk factors and prevention of Type 2 diabetes and overall health and longevity

Angulo and Lindor, Sem Liver Disease 2001

DRUGS ‘EVALUATED’ IN THE TREATMENT OF NAFLDAUTHOR DRUG PATIENTS ALT HISTOLOGYLaurin et al 1996 UDCA 24 improved improved

Laurin et al 1996 Clofibrate 16 no no

Guma et al 1997 UDCA 24 improved ND

Ceriani et al 1998 UDCA 31 improved ND

Gulbahar et al 2000 NAC 11 improved ND

Lavine et al 2000 Vit E 11 improved ND

Caldwell et al 2001 Troglitazone10 improved improved

Hasewaga et al 2001 Vit E 22 improved improved

Marchesini et al 2001 metformin 14 improved ND

Neuschwander-Tetri 2002 rosiglitzone 30 improved ND

Nair et aal 2002 metformin 25 improved ND

1. Control risk factors- 10% decrease in BMI- Aerobic exercise 30 min 4x/week- statins where indicated- treatment of diabetes

2. If no response after six months and at higher risk of fibrosis- liver biopsy to distinguish steatosisversus steatohepatitis (prognosis)- add non-evidence based therapy

Therapeutic Approach

Natural history: Risk factors for fibrotic diseaseAdapted from Angulo et al. Hepatology 1999;30:1356

DIABETES/OBESITYNo Yes

<45

>45

AST/ALT

<1

>1

<1

>1

0

0

12

13

4

50

47

66

Number represents % of patients with NAFLD on imagingstudy who had significant fibrosis on biopsy

AGE