Epidemiology of the Metabolic Syndrome in the USA Incidence ? Prevalence Distribution Control ? Incidence ? Prevalence Distribution Control ? Epidemiology.

Epidemiology of the Metabolic Syndrome in the USA

• Incidence ?

• Prevalence

• Distribution

• Control ?

• Incidence ?

• Prevalence

• Distribution

• Control ?

Epidemiology Evaluates a Disease

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

The Metabolic Syndrome

Obesity Diabetes

HyperlipidemiaHypertension

Insulin Resistance


What is It ?





- Cardiac

- Diabetes


Metabolic Syndrome

• World Health Organization (WHO)

• International Diabetes Association (IDF)

• Adult Treatment Panel (ATP III)

-National Cholesterol Education Program Expert Panel

• World Health Organization (WHO)

• International Diabetes Association (IDF)

• Adult Treatment Panel (ATP III)

-National Cholesterol Education Program Expert Panel

There are 3 Definitions

Three Different Definitions

Obesity

BP

Fasting Glucose

Triglycerides

HDL Cholesterol

Micro Albumin

BMI

Similar

IPG/HOMA

Same

Not Used

Used

BMI

Similar

IPG/HOMA

Same

Not Used

Used

Central

Same

>6.1mol/L

Same

Similar

Not Used

Central

Same

>6.1mol/L

Same

Similar

Not Used

IDF WHOATP

Central

Same

>5.6mol/L

Same

Similar

Not Used

Central

Same

>5.6mol/L

Same

Similar

Not Used

Concerns About the Metabolic Syndrome

• 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

• 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

(ADA and EASD)(ADA and EASD)


What is It ?





- Cardiac

- Diabetes


Prevalence (%) of Metabolic Syndrome

Country ATP IDF WHO

South Asia 26 18 23

Australia 19 16 21

France 9 13 18

Italy 18 34

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


What is It ?





- Cardiac

- Diabetes


Metabolic Syndrome Predicts All Cause Mortality (13 year Follow up)

Metabolic Syndrome

No Yes

ATP III (%) 10 21 p<0.01

WHO (%) 10 18 p<0.05

Metabolic Syndrome and Cardiac Death

0.8

0.85

0.9

0.95

1

0 2 4 6 8 10 12 14 16

No

Yes

Years Of Follow-Up

NCEP-MetS

Metabolic Syndrome Predicts Diabetes (8 year Follow up)

Diabetes

No Yes

ATP III (%) 14.4 28.7 p<0.0001

WHO (%) 12.5 41.3 p<0.0001


What is It ?





- Cardiac

- Diabetes


Non-Alcoholic Fatty Liver Disease

• What is it?

• Why is it Important?

• How do you treat it?

• What is it?



Proposed Classification for NAFLD*

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

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

PrimaryPrimarySecondarySecondary

• DRUGS

- Corticosteroids - Synthetic Estrogens - Amiodarone - Perhexiline - Nifedipine

• DRUGS

- Corticosteroids - Synthetic Estrogens - Amiodarone - Perhexiline - Nifedipine

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

• 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

• MISCELLANEOUS

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

Non-Alcoholic Fatty Liver DiseaseNon-Alcoholic Fatty Liver Disease

NASHNASH

INFLAMMATIONINFLAMMATION

STEATOSISSTEATOSIS

Non-Alcoholic Fatty Liver(NAFL)

Non-Alcoholic Fatty Liver(NAFL)

Type 1Type 2Type 3Type 4

Type 1Type 2Type 3Type 4

- Fat alone- Fat + Inflammation- Fat + Hepatocyte Injury- Fat + Fibrosis and/ or Mallory Bodies

- Fat alone- Fat + Inflammation- Fat + Hepatocyte Injury- Fat + Fibrosis and/ or Mallory Bodies

NAFLD Activity Score (NASH CRN)

GradeGrade

SteatosisInflammationBallooning Injury

Maximum Score

SteatosisInflammationBallooning Injury

Maximum Score

0 - 30 - 30 - 2

8

0 - 30 - 30 - 2

8

Histologic FindingHistologic Finding

NASH Requires a Score of 4 with at least 1 Point from Ballooning InjuryNASH Requires a Score of 4 with at least 1 Point from Ballooning Injury

WHAT IS NON-ALCOHOLIC?WHAT IS NON-ALCOHOLIC?

Benefits of BeerBenefits of Beer

• Religion

• Patriot

• Government

• Religion

• Patriot

• Government

9 Patron Saints

Ben Franklin

NIAAA

9 Patron Saints

Ben Franklin

NIAAA

Beer Is Proof That God Loves UsAnd Wants Us To Be Happy

Beer Is Proof That God Loves UsAnd Wants Us To Be Happy

- Ben Franklin- Ben Franklin

Relative Mortality (All Causes)

Wine DrinkersWine Drinkers

0 1-7 8-21 22-35 350 1-7 8-21 22-35 35

1.6

1.4

1.2

1.0

0.8

0.6

0.4

1.6

1.4

1.2

1.0

0.8

0.6

0.4

Non WineDrinkersNon WineDrinkers

Risk Factors for Fibrosis in NAFLD

OR 95%CI P

Age, years 1.07 1.04 – 1.08 <0.0001

Diabetes, yes vs. no 2.54 1.75 – 3.69 <0.0001

Alcohol usage, not abstinentvs abstinent 0.53 0.37 – 0.75 0.0004

Benefits of Alcohol in NonAlcolic Fatty Liver Disease

• Improves Insulin Resistance

• Decreases ALT

• Less NASH in Bariatric Surgery Pts

• Less Fibrosis in Nash CRN

• Improves Insulin Resistance

• Decreases ALT

• Less NASH in Bariatric Surgery Pts

• Less Fibrosis in Nash CRN

Practical ConclusionsPractical 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

• 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


• What is it?



• What is it?



The Importance of Any Disease


• Natural History• Prevalence

• Natural History• Prevalence

Determined by:Determined by:

Progressive FibrosisSteatosis Alone

Teli(1995)

1/40

Teli(1995)

1/40

(10 Year Follow-Up)(10 Year Follow-Up)

Matteoni(1999)

2/49

Matteoni(1999)

2/49

Dam-Larsen(2003)

1/109

Dam-Larsen(2003)

1/109

Matteoni Follow-up

(n = 174)NASH Steatosis Indeterminant

(66) (75) (32)

Mortality 16% 2% 0%

(LR)

Confirmed by Kaplan Meier .0043

Natural History of NASH

Sub-AcuteFailure

Sub-AcuteFailure

CIRRHOSISCIRRHOSIS

HCCHCC Post-OLTXRecurrencePost-OLTXRecurrence

Liver RelatedDeath

Liver RelatedDeath

NASHNASH

20%20% 30 - 40%30 - 40%

(2%)(2%)(8%)(8%) ??

Su r

viva

l (%

)S

u rvi

val (

%)

1.0

0.8

0.6 0.4

0.2

0

1.0

0.8

0.6 0.4

0.2

0

0 2 4 6 8 10 12 14 160 2 4 6 8 10 12 14 16

Time (years) Time (years)

Expected Expected

Observed Observed

p = 0.005 p = 0.005

Adams, 2005

Survival in NAFLD

Time (years)Time (years)

1.0

0.8

0.6

0.4

0.2

0

1.0

0.8

0.6

0.4

0.2

0

0 5 10 15 200 5 10 15 20

NAFLD patients

Referencepopulation

NAFLD patients

Referencepopulation

Ekstedt, 2006

Survival in NAFLD

n=129


1.0

0.8

0.6

0.4

0.2

0

1.0

0.8

0.6

0.4

0.2

0

0 5 10 15 200 5 10 15 20

Steatosis

Referencepopulation

Steatosis

Referencepopulation

Ekstedt,2006

Survival in Steatosis


1.0

0.8

0.6

0.4

0.2

0

1.0

0.8

0.6

0.4

0.2

0

0 5 10 15 200 5 10 15 20

NASH

Referencepopulation

NASH

Referencepopulation

Ekstedt, 2006

Survival in NASH

p<0.01

Subjects with NAFLD have a greater than expected mortality compared to matched

controls

• Risk factors for mortality:– Diabetes (p< 0.005)– Age (p < 0.001)– Cirrhosis (p< 0.02)

• Increased mortality:*– cardiovascular disease– liver diseaseAdams et al, Gastroenterology, 2005, 129:113-121

* Ekstedt et al, Hepatology, 2006, 44:865-873* Sanyal et al, Hepatology, 2006, 43:682-689

SUMMARYSUMMARY

• 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



• The Prevalence is High and Increasing World Wide



• Prevalence• Natural History

• Prevalence• Natural History

Determined by:Determined by:

Metabolic Syndrome(NHANES III, 1988-1994)

OVERALL PREVALENCE24%

Diagnosis Based on Elevated Serum Enzymes

Dallas Heart Study

Hepatic TriglycerideContent (%) *

Hepatic TriglycerideContent (%) *

HepaticSteatosis (%)

HepaticSteatosis (%)

All

Black

White

Hispanic

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)

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

31

24

33

45

Browning, 2005Browning, 2005

* Based on NMR and presented as Median (interquartiles)* Based on NMR and presented as Median (interquartiles)

SubjectsSubjects

Prevalence of NAFLD(Updated)

Prevalence of NAFLD(Updated)

Steatosis

30%

Steatosis

30%

NASH

6-8%

NASH

6-8%

Epidemiology of NAFLD

USA

Italy

Japan

Taiwan

India

USA

Italy

Japan

Taiwan

India

Cases(in millions)

Cases(in millions)

Country Country

90

17

78

8

240

90

17

78

8

240

30

30

30

37

24.5

30

30

30

37

24.5

Prevalence(%)

Prevalence(%)

SUMMARYSUMMARY



• The Prevalence is High in the United States and Increasing World Wide


NAFLD Diabetes

CancerCardiovascular

Metabolic Syndrome

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)

Metabolic Syndrome

BMI

Waist(cm)

% Hypertension

% Low HDL

% Hyperglycemia

HOMA-R %

Metabolic Syndrome(%)

Fatty Liver (n=63)

NASH(n=110)

28

96

53

57

60

3.2

67

29

100

72

76

91

4.2

88

Marchesini, 2003


NAFLD Diabetes


Metabolic Syndrome

NAFLDNAFLD

Age at DiagnosisFemalesBMITriglyceridesDevelopment of CirrhosisLiver Related Deaths

Age at DiagnosisFemalesBMITriglyceridesDevelopment of CirrhosisLiver Related Deaths

Diabetes(n=42)

Diabetes(n=42)

37 ± 1167%

31 ± 5489 ± 312

23.9%19%

37 ± 1167%

31 ± 5489 ± 312

23.9%19%

54 ± 1447%

29 ± 6226 ± 115

10.6%2%

54 ± 1447%

29 ± 6226 ± 115

10.6%2%

NS.04.02.04

.05

.02

NS.04.02.04

.05

.02

No Diabetes(n=42)

No Diabetes(n=42) P ValueP Value


NAFLD Diabetes


Metabolic Syndrome

RISK OF CARDIOVASCULAR DISEASE

Type 2 Diabetes

Odds ratio

NAFLD present 1.84 (2.4-2.1) p <.04 1.96(1.4-2.7) p <.001

Adjusted for 1.54 (1.2-1.7) p = .02Metabolic 1.87 (1.2-2.6) p>.001Syndrome

Targher, 2005,2007


• What is it?



• What is it?



Emerging TherapiesEmerging Therapies

RevisitCommon Sense

RevisitCommon Sense

CurrentStrategiesCurrent

Strategies New IdeasNew Ideas

• Diet• Supplements• Co-Morbidities

• Diet• Supplements• Co-Morbidities

• Insulin Resistance• Anti-cytokines• Anti-oxidants

• Insulin Resistance• Anti-cytokines• Anti-oxidants

• Inflammation• Apoptosis• Nuclear Receptor Ligands

• Inflammation• Apoptosis• Nuclear Receptor Ligands

Weight Loss and NASH

Weight Improved

Loss(%) Histology

Life Style Change 9.3 Yes

Control 0.25 No

Hepatology 2010;51:121-129

Primary Outcome –Vitamin E alone met

the pre-specified primary endpoint

Vit E placebo Pio0

10

20

30

40

50

treatment groups

Pro

po

rtio

n o

f su

bje

cts

(%)

P< 0.001 (P< 0.04)

36/84NNT=4.4

26/80NNT= 6.6

16/83

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

Prevention of Insulin Mediated Disease

Environment / Genes

Normal IROS

Obesity DiabetesHypertensionDyslipidemiaVascular diseaseLiver diseaseCancer National Screening

Early Counseling

X

Epidemiology of the Metabolic Syndrome in the USA Incidence ? Prevalence Distribution Control ? Incidence ? Prevalence Distribution Control ? Epidemiology.

Documents

metabolic syndrome criteria

definitions slide

easd slide

cardiac diabetes

used bmi similar ipghoma

treating ms

clinical outcomes

unclear criteria