Disclosures Post-transplant metabolic syndrome Robert H. Lustig, - - PDF document

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Post-transplant metabolic syndrome

UCSF Transplant Symposium, Sept. 21, 2018

Robert H. Lustig, M.D., M.S.L. Division of Endocrinology, Department of Pediatrics Institute for Health Policy Studies University of California, San Francisco Adjunct Faculty, UC Hastings College of the Law Chief Science Officer, Eat REAL

Disclosures

BIO BIOLUMEN Te Technologies

NAFLD and Metabolic Syndrome are congruent (if not the same)

Adults: Marchesini et al. Hepatology 37:917, 2003 Children: Schwimmer et al. Circulation 118:277, 2008

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Metabolic Syndrome: where all the money goes (75% of all healthcare dollars)

Diabetes* Hypertension Lipid abnormalities Cardiovascular disease Non-alcoholic fatty liver disease* Polycystic ovarian disease Chronic renal failure* Cancer Dementia

*transplantable

Thoefner et al, Tranplant Rev 32:69, 2018

But what is Metabolic Syndrome? And what is Post-Transplant Metabolic Syndrome (PTMS)? Is it substantially different?

Cytokines

The standard model of metabolic syndrome

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Cytokines

The standard model of metabolic syndrome

Cytokines

The standard model of metabolic syndrome It’s about obesity —

• r is it?

Basu et al. PLoS One 8:e58783, 2013 Basu et al. PLoS One 8:e58783, 2013

It’s about obesity —

• r is it?

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Basu et al. PLoS One 8:e58783, 2013

It’s about obesity —

• r is it?

Basu et al. PLoS One 8:e58783, 2013

It’s about obesity —

• r is it?

Obesity is the problem (?)

• Obesity is increasing worldwide by 2.78% per year

1975-2015 Lancet Oct 10, 2017 http://dx.doi.org/10.1016/S0140-6736(14)60460-8

• Diabetes is increasing worldwide by 4.07% per year
• 1980-2014 Lancet Apr 6, 2016
• http://dx.doi.org/10.1016/S0140-6736(16)00618-8

Menke et al. JAMA 314:1021, 2015, doi:10.1001/jama.2015.10029

Secular trend in diabetes among U.S. adults, 1988-2012

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Menke et al. JAMA 314:1021, 2015, doi:10.1001/jama.2015.10029

Secular trend in diabetes among U.S. adults, 1988-2012

25% increase in obese

Menke et al. JAMA 314:1021, 2015, doi:10.1001/jama.2015.10029

Secular trend in diabetes among U.S. adults, 1988-2012

25% increase in obese 25% increase in nl wt

Familial Partial Lipodystrophy: Dunningan or Type 2

• X-linked or autosomal dominant
• Absence of limb fat

Easily visible veins Defined musculature

• Minimal visceral fat
• Normal or excess facial fat
• Cushingoid facies (moon facies)
• Dorsocervical fat pad
• Acanthosis nigricans
• Metabolic Syndrome

Peters et al. Nature Genet 18:292, 1998

• Fat mass
• Leptin
• Adiponectin
• Inflam. Cytokines
• Metabolic Syndrome

Comparison between lipodystrophy and obesity

Asterholm et al. Drug Disc Today Dis Models 4:17, 2007

LD

• besity

± +++

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• Fat mass
• Leptin
• Adiponectin
• Inflam. Cytokines
• Metabolic Syndrome

Comparison between lipodystrophy and obesity

Asterholm et al. Drug Disc Today Dis Models 4:17, 2007

LD

• besity

±

So the metabolic syndrome can arise from too much, or too little fat i.e. it’s not the fat that counts

+++ Obesity Lipodystrophy Insulin Resistance

Chehab, Endocrinol 149:925, 2008

Obesity and lipodystrophy share insulin resistance OGTT in ‘healthy’ volunteers from ~1970 till 2014

IGT‐’pre‐diabetic’

So in 40‐50 years our need for insulin increased 2‐4 fold: e.g. did we became 2‐4 fold more insulin resistant?

OGTT in ‘healthy’ volunteers from ~1970 till 2014

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“Exclusive” view of obesity and metabolic dysfunction

Obese (30%) Normal weight (70%) 240 million adults in U.S. 72 million 168 million Obese (30%) Obese and sick (80% of 30%) Normal weight (70%) 240 million adults in U.S. 72 million 168 million Total: 57 million sick

“Exclusive” view of obesity and metabolic dysfunction

Obese (30%) Normal weight (70%) 240 million adults in U.S. 72 million 168 million

“Inclusive” view of obesity and metabolic dysfunction

Obese (30%) Normal weight (70%) 240 million adults in U.S. Normal weight, Metabolic dysfunction (40% of 70%) Obese and sick (80% of 30%) 57 million 67 million Total: 124 million sick 72 million 168 million

“Inclusive” view of obesity and metabolic dysfunction

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Relation between visceral and subcutaneous obesity: (thin on the outside, fat on the inside)

Thomas et al. Obesity doi: 10.1038/oby.2011.142, 2011

White Adipocyte

Burn fat, L

• se we ight

Br

• wn

Adipocyte

NE

Lipolysis, proliferation -ADR

STRESS

-ADR

thermogenesis

Visceral fat can be due to chronic stress

Y2R

Gro w fat, gain we ight

Y2R NPY

Angiogenesis Lipid storage

Pre-adipocyte Proliferation, Adipocyte differentiation

Zukowska, Science 2008

Intrahepatic fat explains metabolic perturbation better than visceral fat

Fabbrini et al. Proc Natl Acad Sci 106:15430, 2009

Hepatic Insulin Sensitivity Index Insulin Stimulated Glucose Disposal Rate Insulin Stimulated Palmitate Suppression Rate VLDL Secretion Rate Contribution Of Free Fatty Acids To VLDL

MRI Fat Fraction Maps

Obese Low Liver Fat = 2.6%

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MRI Fat Fraction Maps

Obese Low Liver Fat = 2.6%

MRI Fat Fraction Maps

Obese Low Liver Fat = 2.6% Obese High Liver Fat = 24%

MRI Fat Fraction Maps

Obese Low Liver Fat = 2.6% Obese High Liver Fat = 24%

MRI Fat Fraction Maps

Obese Low Liver Fat = 2.6% Obese High Liver Fat = 24% Thin High Liver Fat = 23%

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MRI Fat Fraction Maps

Obese Low Liver Fat = 2.6% Obese High Liver Fat = 24% Thin High Liver Fat = 23% New York Times, April 17, 2011 Nature 487:27-29, Feb 1, 2012

Sugar is toxic unrelated to calories

Lustig et al. Obesity 24:453, 2016 Schwarz et al. Gastroenterology 153:743, 2017 Gugliucci et al. Atherosclerosis 253:171, 2016

Strategy

• Isocaloric fructose restriction x 9 days in children who are

habitual sugar consumers

• No change in weight
• Substitute complex carbs for sugar
• Maintain baseline macronutrient composition of the the

diet

• Study in PCRC at Day 0 and Day 10
• Assess changes in organ fat, de novo lipogenesis, and

metabolic health

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Fasting Labs

Day 0 Day 10 β-coefficient (Adjusted Change) [95% CI] p value

Heart rate (bpm)

83.1 ± 10.7 80.1 ± 11.3 ‐2.8 [‐6.5, +0.9] 0.13

Systolic BP (mmHg)

122.6 ± 10.5 121.1 ± 9.9 ‐ 1.39 [‐4.9, +2.1] 0.43

Diastolic BP

68.8 ± 8.9 63.7 ± 7.5 ‐ 4.9 [‐8.1, ‐1.8] 0.003

Fasting lactate (mmol/L)

1.2 ± 0.4 0.9 ± 0.3 ‐0.3 [‐0.5, ‐0.2] <0.001

Lactate AUC (mM/120 min)

160.0 ± 34.5 129.0 ± 34.5 ‐31.2 [‐41.9, ‐20.5] <0.001

HOMA‐IR¥

7.9 ± 4.8 5.2 ± 2.6 ‐2.7 [‐3.8, ‐1.5] <0.001

AST (U/L) *

27.4 ± 14.1 23.8 ± 8.9 0.02

ALT (U/L) ¥

28.9 ± 22.8 26.7 ± 19.6 ‐2.2 [‐4.7, +0.3] 0.09

Fasting TG (mM)

1.4 ± 0.9 1.0 ± 0.5 ‐0.4 [‐0.6, ‐0.2] 0.002

Fasting LDL‐C (mM)

2.4 ± 0.6 2.1 ± 0.6 ‐0.3 [‐0.4, ‐0.1] <0.001

Fasting HDL‐C (mM)

1.2 ± 0.2 1.0 ± 0.2 ‐0.1 [‐0.2, ‐0.1] <0.001

Fasting FFA (mM)

0.6 ± 0.2 0.7 ± 0.2 +0.1 [+0.1, +0.2] <0.001

DNL is the Conversion of Dietary Carbohydrates into Lipids

Into Fat (lipids)

*) *) *) *) *) *) *) *) *) *) *) *) * *) *) *) *) *) *) *) *

Sugar

Fructose

*)

Palmitate

* * *

Acetate

*)

New Tracer Method using MIDA: Hellerstein and Neese, AJP 1999

20 40 60 80 100 120 140 160 Day 0 Day 10

DNL AUC Pre and Post Fructose Restriction

Endocrine Society, March 5, 2015

Oral glucose tolerance test before and after isocaloric fructose restriction

Lustig et al. Obesity Society Nov. 4, 2015

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Changes in liver, visceral, and subcutaneous fat (n = 37)

Ac CoA* Malonyl CoA Glycerol-P Fatty Acid*

TG*

De novo Lipogenesis DNL

VLDL*

Ac CoA* Malonyl CoA Glycerol-P Fatty Acid*

TG*

De novo Lipogenesis DNL

VLDL*

9 days fructose restriction

Ac CoA* Malonyl CoA Glycerol-P Fatty Acid*

TG*

De novo Lipogenesis DNL

VLDL*

LIVER FAT DNL

VLDL*

9 days fructose restriction

Visceral fat

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Ac CoA* Malonyl CoA Glycerol-P Fatty Acid*

TG*

De novo Lipogenesis DNL

VLDL*

Improved Insulin kinetics

LIVER FAT DNL

VLDL*

9 days fructose restriction

Visceral fat

Sugar and disease

• Causation

– Diabetes – Heart Disease – Fatty Liver Disease – Tooth Decay

• Correlation

– Cancer – Dementia

A different model of insulin resistance

Cytokines

Fructose Alcohol Fatty liver

Sensitivity Hepatic insulin resistance

A different model of insulin resistance

Cytokines

Fatty liver

Sensitivity Hepatic insulin resistance

Fructose Alcohol

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A different model of insulin resistance

Cytokines

Fatty liver

Sensitivity Hepatic insulin resistance

Fructose Alcohol

Actually 3 metabolic syndromes

• SQ fat — the ”bucket” hypothesis
• Visceral fat — the “stress” hypothesis
• Liver fat — the “mainlining” hypothesis

ROS

FRUCTOSE

ROS ROS

Mitochondria Peroxisome

ROS

UPR Cell death FRUCTOSE

Acetyl-CoA ROS ATP ROS

Cellular/ metabolic dysfunction

NH2

Endoplasmic Reticulum

Acyl-CoA Lipid droplet pSer-IRS-1 PKC JNK1

Insulin resistance Fat deposition Insulin Receptor

Toward a unifying hypothesis of metabolic syndrome

Bremer et al., Pediatrics 129:557. 2012

But what about post-transplant metabolic syndrome (PTMS)?

If you do a liver transplant, shouldn’t the metabolic syndrome get better?

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Possible causes of post-transplant metabolic syndrome (PTMS)

• Whatever caused the pre-transplant metabolic syndrome in

the first place (e.g. alcohol, sugar)?

• Steroids — only 5% of pts on prednisone, and <5 mg/day
• Post-transplant obesity
• Calcineurin inhibitors

Best to figure this out in children Work of Dr. Emily Perito, UCSF Ped GI

Obesity is not the reason for PTMS

Perito et al. Am J Transplant 16:1909, 2016 Perito et al. Liver Transplantation 23:957, 2017

Retrospective analysis of hepatic steatosis in 318 pediatric liver transplant recipients

Defects in insulin secretion in PTMS

Perito et al. J. Pediatr 182:223,2017

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Insulin secretory dysfunction related to number of years post-transplant and trough tacrolimus level

Perito et al. J. Pediatr 182:223,2017

Effects of calcineurin inhibitors

• n glucose dynamics

Chakkera et al. Clin Pharm Ther 101:114, 2017

Impact of calcineurin inhibitors

Perito et al. Am J Transplant 16:1909, 2016

Summary

• Metabolic syndrome continues to increase in prevalence
• Metabolic syndrome may ultimately result in transplantation
• Three different fat depots are implicated:

– SQ fat (“bucket” hypothesis) – Visceral fat (“stress” hypothesis) – Liver fat (“mainlining” hypothesis)

• All can lead to liver dysfunction, hyperinsulinemia, and chronic

metabolic disease

• Many patients with metabolic syndrome will progress and require

transplantation

• Calcineurin inhibitors, by limiting -cell insulin responsiveness,

complicate the phenotype even further

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UCSF Emily Perito, M.D., M.A.S. Philip Rosenthal, M.D. Mel Heyman, M.D. Ayca Erkin-Cakmak, M.D., M.P.H. Vickie Feldstein, M.D. Touro University Dept. of Biochemistry Jean-Marc Schwarz, Ph.D. Alejandro Gugliucci, Ph.D. SFGH Depts. of Medicine & Radiology Susan Noworolski, Ph.D. Kathleen Mulligan, Ph.D. Stanford Prevention Institute Sanjay Basu, M.D., Ph.D.

Collaborators