Epidemiology of the Metabolic Syndrome in the USA

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Epidemiology of the Metabolic Syndrome in the USA
Epidemiology Evaluates a Disease

• Incidence ?
• Prevalence
• Distribution
• Control ?

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Epidemiology of the Metabolic Syndrome
What is It ?
Why are its Limitations ?
Why is It Important ? What is its Prevalence
? What are its Clinical Outcomes ? -
Cardiac - Diabetes -
Nonalcoholic Fatty Liver Disease

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The Metabolic Syndrome
Obesity
Diabetes
Insulin Resistance
Hyperlipidemia
Hypertension
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Epidemiology of the Metabolic Syndrome
What is It ?
Why are its Limitations ?
Why is It Important ? What is its Prevalence
? What are its Clinical Outcomes ? -
Cardiac - Diabetes -
Nonalcoholic Fatty Liver Disease

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Metabolic Syndrome
There are 3 Definitions

• World Health Organization (WHO)
• International Diabetes Association (IDF)
• Adult Treatment Panel (ATP III)
• -National Cholesterol Education Program
  Expert Panel

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Three Different Definitions
IDF
WHO
ATP
Obesity BP Fasting Glucose Triglycerides HDL
Cholesterol Micro Albumin
Central Same gt6.1mol/L Same Similar Not
Used
BMI Similar IPG/HOMA Same Not
Used Used
Central Same gt5.6mol/L Same Similar Not
Used
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Concerns About the Metabolic Syndrome
(ADA and EASD)

• Criteria are Ambiguous
• Rationale for Thresholds ill defined
• Inclusion of Diabetes Questionable
• Importance of Insulin Resistance Unclear
• Questions about CVD Risk Factors Remain
• Treating MS no different than treating its
  parts
• Medical Value of Diagnosing MS is Unclear

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Epidemiology of the Metabolic Syndrome
What is It ?
Why are its Limitations ?
Why is It Important ? What is its Prevalence
? What are its Clinical Outcomes ? -
Cardiac - Diabetes -
Nonalcoholic Fatty Liver Disease

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Prevalence () of Metabolic Syndrome

• Country ATP IDF
  WHO
• South Asia 26 18
  23
• Australia 19 16
  21
• France 9 13
  18
• Italy 18
  34

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Prevalence () of Metabolic Syndrome
United States and China
County ATP
IDF WHO USA
National 24
40 Texas 25

25 China Hong Kong 17

21 InterAsia 14
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Epidemiology of the Metabolic Syndrome
What is It ?
Why are its Limitations ?
Why is It Important ? What is its Prevalence
? What are its Clinical Outcomes ? -
Cardiac - Diabetes -
Nonalcoholic Fatty Liver Disease

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Metabolic Syndrome Predicts All Cause Mortality
(13 year Follow up)
Metabolic
Syndrome No
Yes ATP III () 10
21 plt0.01 WHO ()
10 18 plt0.05
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Metabolic Syndrome and Cardiac Death
NCEP-MetS
Years Of Follow-Up
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Metabolic Syndrome Predicts Diabetes (8 year
Follow up)

Diabetes No
Yes ATP III () 14.4
28.7 plt0.0001 WHO ()
12.5 41.3 plt0.0001
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Epidemiology of the Metabolic Syndrome
What is It ?
Why are its Limitations ?
Why is It Important ? What is its Prevalence
? What are its Clinical Outcomes ? -
Cardiac - Diabetes -
Nonalcoholic Fatty Liver Disease

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Non-Alcoholic Fatty Liver Disease

• What is it?
• Why is it Important?
• How do you treat it?

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Proposed Classification for NAFLD
Primary
Secondary

• Conditions associated
• with an insulin
• resistance syndrome
• - Diabetes mellitus
• (type II)
• - Obesity
• - Hyperlipidemia

• DRUGS
• - Corticosteroids
• - Synthetic
• Estrogens
• - Amiodarone
• - Perhexiline
• - Nifedipine

• SURGICAL
• PROCEDURES
• - Gastroplexy
• - Jejunoileal
• bypass
• - Extensive
• small bowel
• resection
• - Bilio-pancreatic
• Diversion

• MISCELLANEOUS
• - Abeta/ hypobeta
• - Weber-Christian
• Disease
• - TPN with
• glucose
• - Environmental
• toxins
• - S. Bowel
• Diverticulosis

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Non-Alcoholic Fatty Liver Disease
STEATOSIS
INFLAMMATION
NASH
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Non-Alcoholic Fatty Liver(NAFL)
Type 1 Type 2 Type 3 Type 4
- Fat alone - Fat Inflammation - Fat
Hepatocyte Injury - Fat Fibrosis and/ or
Mallory Bodies
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NAFLD Activity Score (NASH CRN)
Histologic Finding
Grade
0 - 3 0 - 3 0 - 2 8
Steatosis Inflammation Ballooning Injury Maximum
Score
NASH Requires a Score of ? 4 with at least 1
Point from Ballooning Injury
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WHAT IS NON-ALCOHOLIC?
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Benefits of Beer

• Religion
• Patriot
• Government

9 Patron Saints Ben Franklin NIAAA
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Beer Is Proof That God Loves Us And Wants Us To
Be Happy
- Ben Franklin
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Relative Mortality (All Causes)
1.6 1.4 1.2 1.0 0.8 0.6 0.4
Non Wine Drinkers
Wine Drinkers
0 1-7 8-21 22-35
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Risk Factors for Fibrosis in NAFLD

• OR 95CI P
• Age, years 1.07 1.04 1.08
  lt0.0001
• Diabetes, yes vs. no 2.54 1.75
  3.69 lt0.0001
• Alcohol usage, not abstinent
• vs abstinent 0.53
  0.37 0.75 0.0004

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Benefits of Alcohol in NonAlcolic Fatty Liver
Disease

• Improves Insulin Resistance
• Decreases ALT
• Less NASH in Bariatric Surgery Pts
• Less Fibrosis in Nash CRN

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Practical Conclusions

• Histologic Definition
• Fat Ballooning Degeneration
• Fat Fibrosis
• Exclusion Limit for Daily Alcohol Use
• 7 units per wk for women
• 14 units per wk for men

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Non-Alcoholic Fatty Liver Disease

• What is it?
• Why is it Important?
• How do you treat it?

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The Importance of Any Disease
Determined by

• Natural History
• Prevalence

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Progressive FibrosisSteatosis Alone
(10 Year Follow-Up)
Teli (1995) 1/40
Matteoni (1999) 2/49
Dam-Larsen (2003) 1/109
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Matteoni Follow-up

• (n 174)
• NASH Steatosis Indeterminant
• (66) (75) (32)
• Mortality 16 2 0
• (LR)
• Confirmed by Kaplan Meier
  .0043

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Natural History of NASH
20
30 - 40
CIRRHOSIS
Liver Related Death
NASH
(2)
?
(8)
Sub-Acute Failure
HCC
Post-OLTX Recurrence
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Survival in NAFLD
1.0 0.8 0.6 0.4 0.2 0
Expected
Observed
Survival ()
p 0.005
0 2 4 6 8 10
12 14 16
Time (years)
Adams, 2005
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Survival in NAFLD
1.0 0.8 0.6 0.4 0.2 0
NAFLD patients Reference population
n129
0 5 10 15
20
Time (years)
Ekstedt, 2006
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Survival in Steatosis
1.0 0.8 0.6 0.4 0.2 0
Steatosis Reference population
0 5 10 15
20
Time (years)
Ekstedt,2006
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Survival in NASH
1.0 0.8 0.6 0.4 0.2 0
NASH Reference population
plt0.01
0 5 10 15
20
Time (years)
Ekstedt, 2006
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Subjects with NAFLD have a greater than expected
mortality compared to matched controls

• Risk factors for mortality
• Diabetes (plt 0.005)
• Age (p lt 0.001)
• Cirrhosis (plt 0.02)
• Increased mortality
• cardiovascular disease
• liver disease

Adams et al, Gastroenterology, 2005, 129113-121
Ekstedt et al, Hepatology, 2006, 44865-873
Sanyal et al, Hepatology, 2006, 43682-689
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SUMMARY

• NASH is Not a Benign Disease
• Cirrhosis Develops in 20-25 of Cases
• -Liver Related Deaths in 10
• The Prevalence is High
  
• and Increasing World Wide

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The Importance of Any Disease
Determined by

• Prevalence
• Natural History

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Metabolic Syndrome(NHANES III, 1988-1994)
OVERALL PREVALENCE 24
Diagnosis Based on Elevated Serum Enzymes
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Dallas Heart Study
Hepatic Triglyceride Content ()
Hepatic Steatosis ()
Subjects
All Black White Hispanic
3.6 (2.1 6.6) 3.2 (2.0 5.3) 3.6 (2.1
7.3) 4.6 (2.6 10.3)
31 24 33 45
Based on NMR and presented as Median
(interquartiles)
Browning, 2005
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Prevalence of NAFLD(Updated)
NASH 6-8
Steatosis 30
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Epidemiology of NAFLD
Cases (in millions)
Country
Prevalence ()

• USA
• Italy
• Japan
• Taiwan
• India

• 90
• 17
• 78
• 8
• 240

• 30
• 30
• 30
• 37
• 24.5

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SUMMARY

• NASH is Not a Benign Disease
• Cirrhosis Develops in 20-25 of Cases
• -Liver Related Deaths in 10
• The Prevalence is High in the United
• States and Increasing World Wide

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The Metabolic Syndrome
NAFLD
Diabetes
Metabolic Syndrome
Cancer
Cardiovascular
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Patient Demographicsin NAFLD Patients

• Study N Age Female Diabetic Obese
  ?TGs
• () () () ()
• Matteoni 132 53 53 33 70 92
• (1999)
• Angulo 144 51 67 28 60 27
• (1999)
• Marchesini 304 42 17 7 25 3
• (2003)
• Angulo 733 48 47 30 60 60
• (2007)
• NASH CRN 1,266 50 64 31 62 55
• (2010)

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Metabolic Syndrome
Fatty Liver (n63)
NASH (n110)
BMI Waist(cm) Hypertension Low HDL
Hyperglycemia HOMA-R Metabolic Syndrome()
28 96 53 57 60 3.2 67
29 100 72 76 91 4.2 88
Marchesini, 2003
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The Metabolic Syndrome
NAFLD
Diabetes
Metabolic Syndrome
Cancer
Cardiovascular
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NAFLD
Diabetes (n42)
No Diabetes (n42)
P Value
37 11 67 31 5 489 312 23.9 19
54 14 47 29 6 226 115 10.6 2
NS .04 .02 .04 .05 .02
Age at Diagnosis Females BMI Triglycerides Develop
ment of Cirrhosis Liver Related Deaths
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The Metabolic Syndrome
NAFLD
Diabetes
Metabolic Syndrome
Cancer
Cardiovascular
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RISK OF CARDIOVASCULAR DISEASEType 2 Diabetes

• Odds ratio
• NAFLD present 1.84 (2.4-2.1) p lt.04
• 
  1.96(1.4-2.7) p lt.001
• Adjusted for 1.54 (1.2-1.7) p .02
• Metabolic 1.87 (1.2-2.6)
  pgt.001
• Syndrome

Targher, 2005,2007
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Non-Alcoholic Fatty Liver Disease

• What is it?
• Why is it Important?
• How do you treat it?

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Emerging Therapies
Revisit Common Sense
Current Strategies
New Ideas

• Diet
• Supplements
• Co-Morbidities

• Insulin Resistance
• Anti-cytokines
• Anti-oxidants

• Inflammation
• Apoptosis
• Nuclear Receptor
• Ligands

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Weight Loss and NASH

Weight
Improved
Loss() Histology Life Style Change
9.3 Yes
Control
0.25 No
Hepatology 201051121-129
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Primary Outcome Vitamin E alone met the
pre-specified primary endpoint
Plt 0.001
(Plt 0.04)
36/84 NNT4.4
26/80 NNT 6.6
16/83
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Vitamin E for NASH

• Vitamin E (800 IU/day), but not pioglitazone (30
  mg/day), was superior to placebo for histological
  improvement as defined as the primary outcome
• Both vitamin E and pioglitazone significantly
  improved
• Steatohepatitis
• Steatosis grade
• Inflammation grade
• NAFLD activity score
• Neither drug improved fibrosis scores

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Prevention of Insulin Mediated Disease
Environment / Genes
IR OS
X
Normal
Obesity
Diabetes Hypertension Dyslipidemia Vascular
disease Liver disease Cancer
National Screening Early Counseling