NAFLD: The Not So Silent Epidemic

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NAFLD The Not So Silent Epidemic

• Shiobhan Weston MB.BCh., FRCPI
• Director, Center for Liver Disease
• Winthrop University Hospital

September 16, 2005
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Prevalence Data
USA Canada Japan France UK Italy Spain Portugal So
uth America Israel
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Adults Prevalence of Overweight 54
(USA) Prevalence of Obesity 22 population
gt age 20
Steatosis 30.1 million obese adults NASH
8.6 million
Angulo, NEJM 2002
Children Prevalence of Overweight 22
Non-Hispanic Blacks (girls)
Mexican-American (boys) Prevalence of Obesity
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NHANES III
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Prevalence Data
Type II DM 28-55
Obesity 60-95
Hyperlipidemia 20-92
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Who Gets This???
WHO Definitions
Class I Obesity BMI 30-34.9 g/m2 Class II
Obesity BMI 35-39.9mg/m2 Class III Obesity
BMI gt 40mg/m2
Classic TRIAD

• Obesity
• Type II Diabetes
• Dyslipidemia

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Metabolic Syndrome
Syndrome of Insulin Resistance
Visceral Obesity
Steatosis NASH
NIDDM
TG HDL
Hypertension
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HISTOPATHOLOGY
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Pathogenesis
2 Hit Paradigm
Second hit Intrahepatic oxidative stress
Lipid peroxidation
TNF-alpha, cytokine cascade
First hit Excess fat accumulation
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Worldwide Demographic Data Adults
Author Country Year N Age
Female NIDDM Obesity Lipids
Expressed as percentages
Ludwig USA. 1980 20 54 65 50 90
67 Itoh Japan 1987 16 52 75 5
100 63 Diehl
USA 1988 39 52 81 55 71
20 Lee USA 1989 49 53 78 51
69 --- Powell Australia 1990 42 49 83
36 95 81 Pinto Portugal 199
6 32 49 75 34 47
28 Bacon USA 1999 132 53 53 33 70
72 Angulo USA 1999 144 51 67 28 60
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Worldwide Demographic Data Children and
Adolescent NAFLD
Author Country year n age range
M/F Obesity IDDM Lipids Moran
USA 1983 3 13 (10-15) 2/1
3 1 2/3 Baldridge USA
1995 14 13 (10-18) 10/4 14
0 5/10 Rashid Canada 2000
36 12 (4-16) 21/15 30 4
18 Manton Australia 2000 17
11 (9-15) 11/6 16 3
5/2 Schwimmer USA 2003 43
30/14
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Histologic Features in Childhood and Adolescent
NAFLD

Author Country Yr n US
NASH Fibrosis Cirrhosis
Moran TN 1983 3
n/a 2/3 2 /3
0 Baldridge Boston 1995 14
24/31 14/14 14 /14 1 Rashid
Canada 2000 36 24/31
21/24 17/24 1 Manton
Australia 2000 17 10/11 8
9 Schwimmer USA
2003 27
27/43 1
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Natural History Data for NAFLD
Author Study Pts Follow-up
Improve No NASH Fibrosis
Cirrhosis
(years)
Teli 1978-95 n40 7-16 46
7.5 30 3 0

Teli et al. Hepatology 1995
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Natural History Data for NASH
Author Study Pts Follow-up N
Improved No Change Fibrosis Cirrhosis

(years)
Lee 1968-82 n49 1.2 - 6.9
12/39 0 58 25
16.6 (1989) Powell 1960-89 n42 1- 9
12/41 8.3 41.6 33
16.6 (1990) Bacon 1990-93 n33 4 -7
2/33 0 50 0
39 (1994)
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Proposed Histologic Spectrum NAFLD
Fat Ballooning Degeneration Fibrosis /-Mallory
Bodies
Fat Inflammation Ballooning Degeneration
Stage IV
Fat Inflammation
Stage III
Stage II
FAT
Stage I
Matteoni et al, Gastroenterol 1999
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Comparison of Outcomes for Individual
Histological Types of NAFLD
Type I Type II Type III Type
IV Outcome (n49) (n10) (n19) (n54) Cirrhos
is 2 (4) 0 (0) 4 (21) 14 (26) Death 16
(33) 3 (30) 5 (26) 24 (44) Liver-related 1/49
(2) 0 (0) 1/19 (5) 7/54 (13)
Matteoni et al. Gastroenterol 1999
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Clinical Outcomes Based on the Presence or
Absence of Necroinflammation
Type I II Type III IV
p-value Cirrhosis 3.4
24.7 (plt0.0001) 5-yr Survival
75.6 70.9
(p0.12) Liver-Related 5.6 30.8
(p0.06) Deaths
11 liver related mortality for those with
hepatocellular necrosis (Type IIIIV)
Matteoni et al. Gastroenterol 1999
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Cryptogenic Cirrhosis

• Derived from Greek kryptos genesis
• 3rd most common indication for transplant
• 7-14 of transplant recipients - Actuarial 1 and
  5 year survival 72 and 58

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Prevalence of Risk Factors for NAFLD among
Patients with Cryptogenic Cirrhosis
Study Population Female Obesity
NIDDM Lipids Ethnicity
Author Female Obese DM
Lipids
Caldwell (1999) Virginia 70 47 53 21 100 Caucasian
Poonawala (2000) Maryland 47 55 47 N/A N/A
Ong (2001) Virginia 60 25 34 N/A 94 Caucasian
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100 60 15
Post-OLT Steatosis Post-OLT Steatohepatitis
NASH
Cryptogenic
NASH
Cryptogenic
Charlton et al. 2002 Ong et. al. 2001
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NASH as a Cause of End-StageLiver Disease

• Primary indication for OLT in 31/1,207 (2.6) of
  patients evaluated at Mayo between 1993-98.
• 16/546 (2.9) underwent transplantation for
  end-stage NASH

Charlton et al. Liver Transpl, 2001
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Post-transplant Allograft Steatosis
Histology Primary
Liver Disease
Grade II Steatosis NASH HCV C2H5 Cholestatic
4 months 60 (N15) 8 (N51) 12 (N40) 4 (N67)
12 months 60 (n15) 15 (n 54) 15 (n40) 5 (n54)
Charlton et al. Liver Transpl, 2001
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Post-transplant Allograft Fibrosis
Histology Primary Liver
Disease
Grade II Fibrosis NASH HCV C2H5 Cholestatic
4 months 20 (N15) 29 (N51) 18 (N40) 19 (N67)
12 months 33 (n15) 46 (n 54) 13 (n40) 15 (n62)

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Post-transplant NASH
Re-transplantation
Cirrhosis
12.5
NASH
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Steatosis
60
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Post-transplant Recurrence of NASH
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Steatosis Increases The Rate of Fibrosis in HCV
Genotype 1b, 10-14 yrs HCV infection
.3 .2 .1 0
Plt0.01
Plt0.05
.23
4 yrs per stage
Change in HAI Score/yrs of infection
0.14
0.12
7 yrs Per stage
8 yrs Per stage
None 1-30 gt30
Hepatocytes with fat
Adinolfi et al, Hepatol 2001
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Role of Familial Factors and Ethnicity (Contd)
Ninety Patients with Nonalcoholic
Steatohepatitis Insulin Resistance, Familial
Tendency, and Severity

• Retrospective review of 90 patients age 14-70
  with NASH seen at liver clinics at University of
  Tennessee or Medical University of South Carolina
• NASH seen in 9 families, either in siblings or
  subsequent generations
• 28 patients had cirrhosis, almost ½ with
  complications of portal hypertension
• Familial clustering was common 18
• Insulin resistance found in 85 tested.

Willner et al, Am J Gastroenterol, 2001
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Distribution of NAFLD by Racial/Ethnic Group
Estimated Alameda County Population (represented
by KP Membership)
NAFLD Study Population
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Distribution of Serum Aminotransferase Levels in
Persons With NAFLD
Mean Value U/L
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Disease Associations in Different Racial /Ethnic
Groups With NAFLD
Caucasian Latino-Hispanic African-American Asian P- value
BMI, mean (kg / m2) 34.0 34.0 37.8 26.7 Plt0.001
NIDDM () 47.9 45.6 50.0 25 P0.03
Lipids () 49.2 43.4 57.1 57.1 NS
Asian versus other groups combined
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Distribution of Gender in Persons with NAFLD
Number of Patients
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Steatosis or NASH?
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Liver Histopathology in Morbidly Obese Patients
Undergoing Roux-en-Y Bypass
Total Normal LFTs Elevated LFTs n68
n-57 n11
Normal Liver Histology 40 40
22 Steatosis
19 19 56 NASH
31 28
22 Bridging fibrosis/cirrhosis 2.9
3.5 0
UCSF Bariatric Database
NAFLD 36/68 (53)
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Potential Pharmacologic Treatment Options for
NALFD

• Insulin Sensitizing Agents
• Troglitazone/Rosiglitazone
• Metformin
• Lipid-Lowering Agents
• Clofibrate
• Gemfibrizole
• Future Potential Treatments
• Antifibrotics
• Probiotics
• Silymarin, SAMe

Membrane-Stabilizing

• Ursodeoxycholic Acid
• Betaine ( SAMe)

Anti-Oxidants

• Vitamin E
• Lecithin
• Vitamin C
• B-Carotene
• Selenium
• Vitamin B Complex

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Drugs Evaluated for NAFLD
Author Treatment Pts
Design Duration LFTs Histology
Laurin,1999 URSO 24
0pen Label 12 mos Yes
Yes Guma,1997 URSO 24
RCT 6 mos Yes
none Ceriani,1998 URSOdiet
31 Open Label 6 mos Yes
none Lauren, 1996 Clofibrate
16 Open Label 12 mos No
none Basaranoglu,1999 Gemfibrozil 46
RCT 1 mo Yes
none Levine, 2000 Vitamin E
11 Open Label 12 mos Yes
none Abdelmalek, 2000 Betaine 24
Open Label 12 mos Yes
Yes Gulbahar, 2000 NAC 11
Open Label 12 mos Yes
none Marchesini, 2001 Metformin 20
Open Label 4mos Yes none
Neuschwander- Tetri, 2001
Rosiglitazone
12 mos Yes Yes Promrat,
2004 Pioglitazone 18 Open Label
12 mos Yes Yes Lindor, 2004
Urso 166 RCT
24mos Yes Yes
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Patient Sources