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