bariatric surgery: techniques and mechanisms of action ... · pseudotumor cerebri immune...

Bariatric Surgery:Techniques and Mechanisms of Action

Walter J. Pories, MD, FACS

1The screen versions of these slides have full details of copyright and acknowledgements


Walter J. Pories, MD, FACSProfessor of Surgery

1

and BiochemistryBrody School of MedicineEast Carolina University

East Carolina

2

University

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4

Obesity trends* among U.S. adultsBRFSS, 2005

(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)

5No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

Eastern North CarolinaUSA

Regions: percent obese (body mass index: x ≥ 30.0)

nt

6

Perc

en

Regions

US (2002) NC (2002) ENC41 (2001-2005)

Piedmont(2001-2005)

Western(2001-2005)




North Carolina 2001 to 2005: total population age-adjusted mortality

due to diabetes mellitus

7

Regional convergence of social issues

5.2 to 8.2%8.2 to 11.6%11.6 to 15.7%>15.7%

Poverty rate

Percent of the population without health insurance

8

Data for 1999Center for Health Services Research and DevelopmentEast Carolina University

Premature mortality

Low

High

11.8 - 1616.1 - 1818.1 - 2020.1 - 23.1

Percent uninsured

1977: 1.2 million people; the nearest medical center 2½ hours away

9

The site of the new medical school




10

11

12




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14

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1978 East Carolina University

17

“Let’s researchtogether”

Obesity?

18




19

• Obesity is the most prevalent, fatal, chronic diseaseof the 21st century, increasing at a rate seen before only in infectious disease

• 64 5% of adult Americans are overweight or obese

Yes, obesity…

20

• 64.5% of adult Americans are overweight or obese, even more in minorities

It’s not just about weight!The co-morbidities are even worse

Diabetes

Sleep apnea

Pulmonary failure

Heart disease

Stroke

Hernias

21

y

Asthma

Hypertension

Infertility

Depression

Arthritis

Pseudotumor cerebri

Immune suppression

Reflux

Stress incontinence

Pulmonary embolism




The intestinal bypass

12 motions/day

Hypo-proteinemia

Liver failure

1950’s

22

Kidney stones

Mineral loss

Not a great answer

1978 - 80

23Mason gastric bypass Greenville gastric

bypass

1960’s

The platinum rules of clinical research

• Standardize: do not change the protocol

• Total integrity

f

24

• Follow forever




The Greenville gastric bypass

10 - 20 ml gastric pouch8 - 10 mm anastomosis40 - 60 cm alimentary loop

25

Total group 1980-1998 = 83116 year cohort = 147

Weight loss after bariatric surgery@ 16 years (95% followup)

Mean weightMean % XS weight loss

Mean BMI

Preop 317 0 51

1 year 199 67 32

262003 Schauer U Pitt – 104 lb106 lb

2 years 194 69 32

5 years 209 57 34

10 years 217 51 35

16 years 211 55 37

27

The Greenville gastric bypass produces durable and safe weight loss




28

A morbidly obese woman who could not conceive…

250

300

LB

The weight loss is sustained

290 1 2 5 10 16

150

200

LB

Years

Mean % weight change over 15 years Swedish obesity study

in w

eigh

t (%

)

Vertical banded gastroplasty

Banding

Control

30

Sjostrom: NEJM 2007;357:741-52

Years

Cha

nge

Gastric bypass

Vertical-banded gastroplasty




1980: the first diabetic patients

1. Normal glucose level after surgery?



31

You don’t know how to work up patients!


Why isn’t the lab giving us reliable values?

Date Glucose Insulin given

16 Nov ‘80 PREOP/OP 495 90

17 Nov 281 818 Nov 308 16

Insulin requirementspre & post gastricb pass

Pt. LT

Remission of diabetes after gastric bypass

32

19 Nov 240 820 Nov 210 421 Nov 230 822 Nov 216 428 Nov 193 030 Nov 153 014 Dec 155 0

bypass

608 morbidly obese

165 Type 2Diabetics

165 IGT“impaired”

146 long enoughfollowup

152 long enoughfollowup

33

121/146 (83%)euglycemic

150/152 (99%)euglycemic

Schauer:1,160 pts.83% remission




78

232 morbidly obese diabetics

154

Gastric BypassOperation refused

34

Gastric Bypassfor personal or insurance reasons

22/78 (28%)/6.2 yrs14/154 (9%)/ 9 yrs

P<0.0003

Mortality

1%/yr 4.5%/yr

Long-term survival CanadaChristou et al., Ann Surg 2004; 240: 416-424

Rel. Risk = 0.11 (.04-.27)

89% reduction in risk of death over 5 years

6.17

6

7

35

of death over 5 years

0.68

0

1

2

3

4

5

% M

orta

lity

Control Bariatric

Unadjusted cumulative mortalitySwedish obesity study

36Sjostrom: NEJM 2007; 357: 741-52




Morbid obesityOperative changes in abdominal pressure

37Sugerman et al.

P<0.0001

Surgically induced weight loss effects on urinary diary parameters

38Sugerman et al.

Before surgery After surgery

39




40

Pulmonary artery pressure before and after surgically induced weight loss

for morbid obesity

41

PaO2 and PaCO2 before and after surgically weight loss for morbid obesity

42




43

Preoperative

After weight loss

44

45




Health problems associated with morbid obesity

Diabetes

Sleep apnea

Pulmonary failure

Congestive heart failure

Stroke ?

Hernias

46

Asthma

Hypertension

Infertility

Depression ?

Arthritis

Pseudotumor cerebri

Immune suppression ?

Reflux

Stress incontinence

Pulmonary embolism

Five year comorbidity comparison

*

*

*

Musculoskeletal

Infectious

Cancer

47

*

*p<0.001Christou et al., Ann Surg 2004; 240: 416-424

0 5 10 15 20 25 30 35 40%

Cardiovascular

Endocrinological

MusculoskeletalControlBariatric

*

What’s going on here?

Let’s go ask a medical student: “What is Diabetes Mellitus?”

48

g




Type 2 diabetes:“Patients don’t make enough insulin…”

Insulin resistance

49

Insulin resistance

Look, type 2 diabetes is due to failure of the islets!

50

Oral glucose tolerance test

Are the islets the problem?

51No; the islets may be sick, but they work;

in fact, Type 2 diabetics are hyper-insulinemic




52Type 2 diabetes: an islet of Langerhans demonstrates amorphous pink deposition of amyloid

53

Type 1 diabetes: an islet of Langerhans demonstrates insulitis with lymphocytic infiltrates in a patient developing type I diabetes mellitus

54

What if insulin resistance is a protective mechanism of the cell against the overproduction of insulin?




If the gut is overstimulating the islets,

55

Then bypassing the gutshould make the insulin levels fall

Response of insulin levels to the GGB

in (μ

U/m

l)

100

60

40

56

Pla

sma

Insu

l

Months postop

-12 0 12 24 36 48 60 72

80

20

0

Too much

Too muchgluconeogenesis

57

insulin

Overwhelmedmitochondria




CHO

Incretins Hormonesfrom fat

So, it’s not just a matter of glucose levels…

58

from fat

CCK GhrelinoleylethanolamideGLIP-1 GLIP-2GIP apo A-IVPPY LeptinPYY etc.

LeptinAdiponectinResistinInflammatory cytokinesetc.Muscle

Neuro-endocrine

Genetic leptin deficiency causes obesity in ob/ob mice

59

From Michael Swart

Leptin receptor mutation causes obesity in db/db mice

60db/db mouse+/+ mouse

From Michael Swart




CHO

Incretins Hormonesf f t

Leptin insulinMC3R, PPARyMC4R. PYY, Neuropeptide YAgouti-related protCiliary neutrophic factors, etc.

Hypothalamus

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from fatCCK GhrelinoleylethanolamideGLIP-1 GLIP-2GIP apo A-IVPPY LeptinPYY etc.

LeptinAdiponectinResistinInflammatory cytokinesetc.Muscle

Neuro-endocrine

Insulin

S SSS S

S

IRS-1/2

NEFA

Fatty acyl-CoA

Glucose

CO2Ser

Ser P

P

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GLUT4

PI3K

PDK

Akt/PKB

aPKCζP

P

PKC (q or b) DAG

TAG

Dohm, GL et al.

Insulin sensitivity in non-diabetic gastric bypass patients (post-surgery)

and non-surgery control subjects

4

5

6

7

8

sitiv

ity In

dex

*

*

63

0

1

2

3

4

Lean Weight-matched Morbidly obese Post-surgery

BMI <25 BMI = 25-35 BMI >35 BMI = 28.5

Insu

lin S

ens

†




Muscle IRS1 serine phosphorylation in non-diabetic gastric bypass patients (post-

surgery) and non-surgery control subjects

11.21.41.61.8

ho-S

er31

2/IR

S1

ry u

nits

)

†

64

00.20.40.60.8

Lean Weight-matched

Morbidly obese Post-surgery

BMI <25 BMI = 25-35 BMI >35 BMI = 29.9

IRS1

-Pho

sph

(arb

itra *

Obese

0

100

200

300

400

500

600

0 30 60 90 120 150 180 210 240 270 300Time (min)

Insu

lin (p

M) Before surgery

Surgery week3 month

65

Diabetic

0

100

200

300

400

500

600

0 30 60 90 120 150 180 210 240 270 300

Time (min)

Insu

lin (p

M)

Before surgerySurgery week3 month

All patients – HOMA

3

4

5

6

7

*#O

MA

66

Pre 1 Wkpost

3 Mopost

0

1

2

3

*#

* p < 0.05# p < 0.05

(n = 6)

H




Obese

0102030405060708090

0 30 60 90 120 150 180 210 240 270 300

Time (min)

GLP

1 (p

M) Before surgery

Surgery week3 month

67

Diabetic

0102030405060708090

0 30 60 90 120 150 180 210 240 270 300

Time (min)

GLP

1 (p

M) Before surgery

Surgery week3 month

50

60

70

80

90

100

M

GLP-1 in response to a meal in non-diabetics

MID DOSE

680

10

20

30

40

50p

Time in minutes

HeadquartersSuppliers

Receiving

69

Jobbers

Warehouse Customers

Insulin Inc.




Restrictive Malabsorptive

70

Gastric bypass

Adjustablegastric band

Verticalbandedgastroplasty

Duodenalswitch

BandingGastric bypass

Duodenal switch

Excess weight

Comparison of bariatric operations: the resolution of diabetes is “dose related”

n = 22,094 patients; 2738 citations 1990-2002

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Excess weight loss

47.5% 61.6% 70.1%

Operative mortality

0.1% 0.5% 1.1%

Resolution of diabetes

47.8% 83.6% 97.9%

Buchwald, Avidor, Braunwald, Jensen, Pories, Farbach, SchoellesJAMA 2004; 292: 1724-1737

Diabetologists maintain that the remission

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is due to weight loss alone; is that true?




Rubino: Goto-Kakizaki Rat (GK)

Animal model of type 2 diabetes

• The most-widely used lean model in type 2 diabetes research

(Nature Genet 1996)

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– Non-obese

– Normolipidemic

– Hyperinsulinism

– Insulin resistance

Rubino: duodenal-jejunal bypass (DJB) in the GK rat

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Rubino: duodenal exclusion in the diabetic non-obese rat

OGTT

300350400450

Diet

Bypass

75P<0.001

050

100150200250

Baseline 10 min 30 min 60 min 120 min 180 min

Bypass

Sham




Rubino: OGTT after duodenal exclusion

69000

OGTTAUC

Duodenal Pass.Duod. Exclus

76Annals of Surgery 2006

P<0.0544000

49000

54000

59000

64000

Duodenal Pass. Duod. Exclus

Rubino, F: Annals of Surgery, Nov 2006

Diabetic lean rats

77Duodenal silastic

tube; Diabetes clears

With perforations, the Diabetes returns

Insulin sensitivity in non-diabetic gastric bypass patients (>12 mo.)

and non-surgery subjects

8

10

12ControlPost bypassLinear (control)Linear (post bypass)

78

0

2

4

6

15.00 25.00 35.00 45.00 55.00 65.00BMI

HO

MA




Interesting;Have there been any studies

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Have there been any studies in non-obese diabetic patients?

Patients Follow-upFasting

Glycemia Pre-op

Fasting GlycemiaPost-op

1. RG 7m 216 98

Duodenal-jejunal lap bypass in lean diabetic patients

Ramos A, Galvao Neto M, Galvao M.

80

2. CD 7m 168 110

3. MC 6m 157 79

4. MM 5m 148 82

5. RD 2m 225 94

6. JG 1m 173 92

Patients Follow-upHbA1c Pre-op

HbA1cPost-op

1. RG 7m 8,6 6,2

Ramos A, Galvao Neto M, Galvao M.

Duodenal-jejunal lap bypass in lean diabetic patients

81

2. CD 7m 7,5 6,0

3. MC 6m 8,2 5,8

4. MM 5m 7,8 6,3

5. RD 2m 8,2 7,6

6. JG 1m 8,7 7,9




Dr M. Lakdawala M.S. India 6 months follow up duodeno-jejunal bypass in lean diabetic patients

Pre-surgery (N = 3) Post surgery (6 months)

BMI1. 27.52. 283. 29.5

27.52729

HbA1C1. 92. 10.4

5.16.3

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3. 9.5 6.0

PP Insulin1. 2402. 2323. 244

59.556.550.0

FBS1. 1282. 1553. 162

959290

PPBS1. 2652. 2443. 275

104134124

Gastrectomy and diabetes

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Surgery, Gynecology & Obstetrics; February 1955

OK, you have my interest; what are the indications for bariatric

surgery today?

• BMI ≥ 40

• BMI ≥ 35 with significant co-morbidities

≥ 18 f

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• ≥ 18 years of age

• Full understanding of surgery and its consequences

• Contract for life-long follow-up

• Supportive family




Which operation is best?

85

48% 84% ?51% 98% ?100%

Rates of remission of Type 2 diabetes

Adjustable gastricband

Gastricbypass

Duodenalswitch

Gastric sleeve

Duodeno-jejunal bypass

OK;but isn’t bariatric surgery dangerous?

86

SRC data: 272 hospitals, 495 surgeons>110,000 patients

Hospital mortality 76 0.14%

Operative mortality at 30 days (76 + 89 = 165) 165 0.29%

87

Operative mortality at 90 days (76+89+31 = 196) 196 0.35%

Re-admissions 1,956 4.75%

Re-operations 887 2.15%




TABLE 2. Mortality rates following common operations in U.S. hospitals

AorticAneur

CABG CraniotEsophagResect

HipReplac

PancPed.Heart

Surgery

Number of hospitals performing operation

2485 1036 1600 1717 3445 1302 458

National average3 9 3 5 10 7 9 1 0 3 8 3 5 4

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mortality rate(%)3.9 3.5 10.7 9.1 0.3 8.3 5.4

Average hospital caseloads median

30 491 12 5 24 8 4

[i] Dimick JB, Welch HG, Birkmeyer JD; Surgical mortality as an indicator of hospital quality; JAMA 2004, 292, 847-851

SRC: bariatric surgery mortality 0.3% (55,567 patients)

106 hospitals reporting average case load: 312 cases/year

Conclusions

• Diabetes is no longer a hopeless disease

• Current medical therapies for diabetes are complex, expensive with little proof that the new medications are better

S f ff f

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• Surgery for diabetes is effective and safe

• Surgery must be considered a therapeutic option

• Bariatric and metabolic surgery offers new research avenues toward the understanding of diabetes

• East Carolina University is a great place; come and visit us

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