Non-alcoholic Fatty Liver Disease (NAFLD) in Children NAFLD... · Non-alcoholic Fatty Liver Disease...

Pediatrics Grand Rounds 18 September 2009

University of Texas Health Science Center at San Antonio

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Non-alcoholic Fatty Liver Disease (NAFLD)

in ChildrenCarisse Orsi, MD

Pediatric Endocrine FellowSeptember 18, 2009

Goals and Objectives

Define NAFLDDiscuss the theories behind the pathophysiology of the diseaseKnow how to diagnose NAFLDUnderstand the disease progressionDiscuss current studies for the treatment of fatty liver

What is Non-Alcoholic Fatty Liver Disease (NAFLD)?

A chronic liver condition characterized by:

Hepatic fat accumulation (in the absence of ethanol abuse & other identifiable causes)

Insulin resistance

Frequently associated with impaired glucose intolerance or type 2 diabetes

NAFLD

Hepatic fat accumulation (steatosis) may range from simple steatosis

Natural history poorly understood, no large long-term studies

Non-Alcoholic Steatohepatitis(NASH)

NASH is fat accumulation plusNecrosisinflammation Fibrosis

May progress to portal hypertension and cirrhosis



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Fatty Liver in AdultsIn adult patients with NAFLD, approximately 30-40% of patients eventually progress to NASH A slightly smaller percentage (10-30%) of adult patients with NAFLD develop cirrhosis after 10 yearsThe most common cause of cirrhosis in adulthood and in childhoodQuestion of if/when patients will develop heptatocellular carcinoma

Fatty Liver in Children

First described in children in 1983In children, the incidence of NAFLD and NASH is ~10% of the pediatric population More common in obese children and those with type 2 diabetesLong-term outcomes of this condition in children are not known, but are likely to be worse due to the anticipated lifespan of the typical adolescent.

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Estimate of Pediatric Obesity Prevalence: 1973-2020

Natural History of Pediatric NAFLD

Not well understoodCase reports of rapid progression to cirrhosis1

106 NAFLD pts (mean 13.4 yrs)2

All baseline liver biopsy18 repeat liver biopsies, mean 28 months

8 pts no change fibrosis7 pts worsening fibrosis3 pts improved fibrosis BUT all lost weight

1Molleston JP et al. Am J Gastro 2002;97:2460-2.2A-Kader HH et al. Clin Gastroenterol Hepatol 2008;6:799-802.

Role of adipose tissue, insulin resistance, fatty acids and

lipotoxicity

Defects at multiple levels may tip the metabolic balance towards hepatic fat accumulation

Excessive substrate supply to the liverIntrahepatic mismatch between lipid synthesis and oxidationInadequate export to peripheral tissues



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Copyright ©2008 The Endocrine Society

Marchesini, G. et al. J Clin Endocrinol Metab 2008;93:s74-s80

Hepatic TG originate either from FFA--accumulating in the liver from recirculation from adipose tissue (namely visceral) or from chylomicron remnants from dietary lipids--or

from de novo lipogenesis from absorbed CHO Proposed Pathophysiology

The expanded liver fatty acid pool leads to increased mitochondrial and peroxisomal beta-oxidation, which produces reactive oxygen speciesMay promote both local proinflammatory state

leading to progressive liver injury release of proinflammatory cytokinesstimulate the production of suppressors of cytokine signaling proteins

Proposed Pathophysiology

An increase in suppressors of cytokine signaling-3 in the liver leads to:

persistent hyperinsulinemiafurther exacerbates insulin resistance

Hyperinsulinemia stimulates the transcription factor sterol regulatory element-binding protein-1c, which leads to:

activation of lipogenic genes a decrease in fatty oxidation

NAFLD in T2DM

In T2DM, chronic hyperinsulinemia and hyperglycemia promote lipogenesis

Upregulating hepatic sterol regulatory element binding protein 1c (SREBP1c) andCarbohydrate regulatory element binding protein (ChREBP) activity

High carbohydrate/fructose-based diets promote de novo lipogenesis and can activate harmful inflammatory pathways with hepatic apoptosis

c-jun N-terminal kinase (JUN)-signaling pathwayIncreased consumption of dietary carbohydrates is common in patients with NAFLD and is associated with increased hepatic mRNA expression of fructokinaseRestriction of dietary carbohydrates reduces hepatic fat and elevated ALT in obese patients with NAFLD

Role of Leptin, Resistin, and Adiponectin

Leptin is a peptide produced primarily in the adipose tissueLeptin deficient mice do not develop NASHStudies have not shown leptin levels are associated with specific liver fibrotic stages



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Resistin

An adipose-derived proteinOverexpression of resistin in mouse models led to glucose intolerance, hyperinsulinemia, and impaired suppression of free fatty acids levels High resistin levels have been associated with hepatic steatosis

Adiponectin

Hormone secreted exclusively by adipose tissueProduces beneficial effects on lipid metabolism, enhancing lipid clearance from plasma and beta-oxidation of fatty acids in muscleDirect anti-inflammatory effects, suppressing TNF-alpha production in the liverAppears to be protective against NASH

Proposed Progression from Adipose tissue to NASH

Step 1: Adipose tissue insulin resistance, provides lipotoxic environment that supplies liver with FFA and compensatory hyperinsulinemia that stimulates lipogenesisStep 2: Development of hepatic steatosisand of a lipid pool from where lipid-derived toxic metabolites may activate inflammatory pathways

Step 3: Progression from simple steatosisto active necroinflammation depends on the ability of the liver to adapt to longstanding triglyceride accumulation

Failure leads to FFA-induced lipotoxicity with mitochondrial dysfunction, endoplasmic reticulum stress, reactive oxygen species (ROS) formation, and chronic necroinflammation

Step 4: Fibrosis, chronic activation of hepatic stellate cells in a poorly understood cross-talk of Kupffer cells with hepatocytes

Who gets NAFLD?

ObeseMetabolic syndromeT2DMAcanthosis nigricansMales > femalesHispanics > Caucasians > AA

San Diego Study

The largest study that has been undertaken on adolescents and NASH in a retrospective autopsy-based evaluation

Performed on 742 children between 2 to 19 years of age Died traumatically (motor vehicle accidents, accidents, homicide or suicide) Individuals were excluded if they had any factors that would potentially influence liver histology (ie. recent inpatient hospital stay or a positive alcohol or drug toxicology screen)

Schwimmer JB, et al. Pediatrics 2006



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San Diego StudyIn this unique group of previously healthy children, 9.6% had evidence of fatty infiltration of the liver as assessed by liver histology Fatty liver disease was more prevalent among those who were older, overweight, and known associations with insulin resistanceFatty liver was also more common in males (10.5 % versus 7.4% in females) and Hispanics (11.8% versus 1.5% in Blacks and 8.6% in non-Hispanic whites)


Age, yb 2–4 0.7 (0.0–2.0)5–9 3.3 (0.0–7.1)10–14 11.3 (4.8–17.8)15–19 17.3 (13.8–20.8)

Genderc Boys 11.1 (8.4–13.8)Girls 7.9 (4.2–11.6)

Race/ethnicityd Asian 10.2 (3.0–17.5)Black, non-Hispanic 1.5 (0.0–4.9)Hispanic 11.8 (7.8–15.8)White, non-Hispanic 8.6 (5.6–11.7)

a Standardized for age, gender, race and ethnicity b Standardized for gender, race, and ethnicity. c Standardized for age, race, and ethnicity. d Standardized for age and gender.

Prevalence of Fatty Liver by Age, Gender, Race, and Ethnicity


Category Age Percent Prevalence 95% CI

San Diego Study

Actual liver inflammation (steatohepatitis, NASH) was found in 23% of children with fatty liver and 3% of the total autopsies

This data is consistent with 3 smaller studies and also confirmed that Hispanics are more likely to develop advanced liver fibrosis


Prevalence of Pediatric NAFLD

Papandreou D et al. Clin Nutrition 2007, 26:409-15.

Country # of subjects

Ages Fatty Liver %

Diagnosis

USA 2450 12-18 3% ALT

USA 742 2-19 9.6% Biopsy

Korea 1594 10-19 3.2% ALT

Japan 810 4-12 2.6% Ultrasound

NASH & Cardiovascular DiseaseCardiovascular Risk Factors and the Metabolic Syndrome in Pediatric Nonalcoholic Fatty Liver

Disease

Aim: To determine the association between NAFLD and the presence of metabolic syndrome in overweight and obese children

Case-control study 5-17 yr old patients150 overweight children with biopsy-proven NAFLD 150 overweight children without NAFLD

Schwimmer JB et al. Circulation 2008;118:277-83



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Cases and Controls

Study patientsBiopsy proven NAFLD based on liver biopsy with > or = 5% hepatocytes containing microvesicular fatExclusion of other causes

Controls Overweight/obese children evaluated for weight management defined at Negative NAFLD = negative liver enzymes with ALT < 30 U/L and no hepatomegaly


Risk factors of Pediatric NAFLD

•Groups similar except NAFLD groups had higher numbers of Asians and Hispanics

•Children with NAFLD had higher glucose, insulin, systolic/diastolic BP, total cholesterol, LDL, TG, and lower HDL

•Adjusting for age, sex, race, ethnicity, BMI, insulin: Children with Metabolic syndrome had 5 x rate of NAFLD


Metabolic syndrome Criteria (3/5 required)

•Abdominal obesity (>102 cm boys, >88 cm girls)•High triglycerides (≥150)•Low HDL (<40 for boy, <50 for girls)•Elevated BP (sys≥135, diastolic≥85)•Impaired fasting glucose (>100)

Diagnosis of NAFLD/NASH

Exam

Laboratory analysis

Imaging

Liver biopsy

Diagnosis NAFLD & NASH

Clinical findings:

Few clinical symptoms (i.e. right upper quadrant discomfort in about 42-59%)

Acanthosis Nigricans

Hepatomegaly

Diagnosis of NAFLD

Laboratory: Elevated ALTMay be associated with elevated liver aminotransferases (ALT>AST)May NOT be associated with an elevation in ALT/AST

Using this tool, in the National Health and Nutrition Examination Survey (NHANES) III, 6% of overweight adolescents and 10% of obese adolescents had elevated levels of ALT

CATCH TrialSmall cohort of 127 12th grade students (BMI ≥30kg/m2) taking part in the Child and Adolescent Trial for Cardiovascular Health (CATCH), 23% had an elevated ALT

Elevated ALT was seen in 36% of Hispanics, 22% of non-Hispanic whites, and 14% of black children

Other studies have shown that 2/3 of pts with NAFLD diagnosis by more definitive and specific tests such as biopsy or imaging have normalliver function tests (LFTs).



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Steatohepatitis in Adult Obese Patients with or without Elevated LFTs: Histological Findings

0

20

40

60

80

100

Steatosis Inflammation Ballooning Fibrosis

Normal LFTsElevated LFTs

N = 58 in each group

Sorrentino P. J Hepatology 2004; 41:751-757

Because NAFLD is a diagnosis of exclusion, we must rule out

other etiologies of chronic liver disease and inflammation.

Etiology of Chronically Elevated Aminotransaminases

Etiology Risk Factors Screening

NAFLD Metabolic Syndrome Imaging, Biopsy

Alcoholic (1:130) Family history History, AST/ALT >1, ↑GGT

Hepatitis C (1:150) IVDU, blood transfusions Hep C Antibody

Medications Exposure history Estrogen, tylenol, propylthiouracil

Hepatitis B (1:350) Endemic area, IVDU Hep B surface antigen

Hemochromatosis(3:1000)

Family history Transferrin saturation, ferritin

α-1 Antitrypsin Ab(1:2500)

Family history α-1 Antitrypsin level and genotype

Autoimmune hepatitis (1:10,000)

Young, female, coexisting autoimmune disease

Anti-nuclear Ab, anti-smooth muscle Ab, Immunoglobulins

Wilson’s disease (1:30,000)

Family history Ceruloplasmin

Modified from Adams LA et al. J Clin Gastroenterol 2006

Associated disorders of pediatric NAFLD•Hypothalamic disorders

•Prader-Willi syndrome

•Genetic disorders•Bardet-Biedl•Alstrom syndrome•Lipodystrophy syndromes•Dorfman-Chanarin syndrome•Cantu syndrome•Polycystic ovary syndrome

Roberts E. J Hepatol, 2007;46:1133-42.

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Pediatric Endocrine NAFLD Work-up

α-1 antitrypsinIronTotal Iron Binding CapacityAntinuclear Antibody (ANA)Anti-smooth muscle antibodyAnti-LKM-1antibodyHepatitis C, B profileCeruloplasmin

If many patients with fatty liver have normal liver enzymes, how

should we diagnose them?



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Imaging NAFLD/NASH

Ultrasound

Computed Tomography (CT)

MRI and spectroscopy

Diagnosis by UltrasoundIn adults, ultrasound of the liver is 60-94% sensitive and 73-95% specific for the diagnosis of liver fat when compared to liver histology With >30% fatty infiltration, sensitivity of ultrasound is 80% With 10-19% fatty infiltration, sensitivity of ultrasound is 55%Sensitivity and specificity of ultrasound decrease due to the presence of morbid obesity to 49% and 75%, respectively

Diffuse fatty change – typical ultrasound appearance with increased reflectivity of the liver parenchyma relative to the adjacent kidney.

http://imaging.birjournals.org/cgi/content-nw/full/16/4/364/F1

Diagnosis by CT

Computed tomography of the liver is 43-95% sensitive and 90% specific for detecting fatty liver

These values are decreased if the fatty liver content is below 30%

Magnetic Resonance Imaging and Spectroscopy (MRS)

New gold standard for imaging diagnosis of NAFLD

The Dallas Heart Study was the first large-scale study to use MRS to measure fatty liver

Szczepaniak, L. S. et al. Am J Physiol Endocrinol Metab 288: E462-E468 2005

Dallas Heart Study

Evaluated 345 subjects with no other identifiable cause of fatty liverFatty liver of 5.5% or greater corresponded to the 95% area of distributionShowed 33.6% of the adult population had hepatic steatosis

Reproducibility r=0.99 p<0.001




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Copyright ©2005 American Physiological Society


Distribution of HTG in the Dallas Heart Study

|

Median

Dallas Heart Study

Prevalence was higher in obese, MS, T2DM, Hispanics and males

Elevated ALT correlated with an increase in liver fat

2/3 of pts with fatty liver have normal liver enzymes


Graph illustrates the MR imaging spectrum of a fatty human liver

Cassidy F H et al. Radiographics 2009;29:231-260

©2009 by Radiological Society of North America Copyright ©2005 American Physiological Society


Experimental set-up for measurements of hepatic triglyceride (HTG) content by proton magnetic resonance

spectroscopy (1H MRS)

Liver Biopsy

Liver biopsy is the only way to differentiate between NASH and hepatic steatosisImaging unable to stage the degree of fibrosisThere are several definitions for the staging of NASHSampling error may lead to variation by one fibrosis stage in 24-37% of biopsies



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Staging of NASH

Pediatric NASH is often histopathologicallydifferent than adult NASH in the degree of and location of fat, inflammation and fibrosis

Typical adult pattern of NASH includes macrovesicular steatosis, lobular inflammation and ballooning degeneration

Pediatric NASH

Portal inflammation (70%) and portal fibrosis (60%) was present in biopsiesTypical adult pattern termed Type 1Type 2: Steatosis with portal inflammation and/or fibrosis

Without perisinusoidal fibrosis or evidence of ballooning degeneration

Type 1 and Type 2 NASHDistinct clinical and demographic differences between children with type 1 and type 2 histologyThis is suggestive of important pathophysiological differences between adult and pediatric NASHChildren with type 2 are

youngergreater severity of obesitymale > female

Distribution of types 1 and 2 NASH by sex (A) and race/ethnicity (B). Data are from a study of children ages 2 to 18 years with biopsy-proven NAFLD.

Percentages within each category of race or sex may not equal 100 because some children were categorized as having either simple steatosis or overlap of type 1 and type 2 histology.

Patton, HM et al. JPed Gastro and Nutr. 2006;43:413-427

Top: Type 1 (adult) NASH typical pattern of macrovesicular steatosiswith portal sparing, perisinusoidal

fibrosis

Bottom: Type 2 (pediatric) NASH marked macrovesicular steatosis

involving nearly all hepatocytes, with portal inflammation and fibrosis


Two pictures of the same male patient 5 years apart:

Top: Age 4Marked macrovesicular steatosis

with portal inflammation

Bottom: Age 9Less steatosis but expanded portal

tracts and fibrous septa




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Elevated LFTS

Pediatric NAFLD Algorithm

Rule out other causes of fatty

liver

Consider Liver Biopsy

NASH

▪Reduce daily caloric intake ▪Exercise

Consider: ▪Clinical treatment trials vs.

intensive diet and exercise

Consider Imaging

Risk factors for Fatty Liver:•Insulin resistance•Obesity•Diabetes

Recheck liver enzymesAfter 3 months

LFTs increasing

NAFLD

What are the treatments options for pediatric patients with NAFLD?

Pediatric NAFLD Ongoing Research

132 studies for “fatty liver treatment”7 studies ongoing for “pediatric fatty liver”

Drugs under investigationAcarbose (pilot study)XenicalMetformin

Other trialsLow glycemic diet vs low fat diet

Torres DM, Harrison SA. Gastro 2008.

Treatment Options

In a 12-month double-blinded placebo study on 90 children with NAFLD

Subjects were placed on a balanced caloric dietPhysical exercise Either placebo or Vitamin E 600 IU/day and Vitamin C 500 mg/day.

Diet and exercise alone was better than antioxidant therapy

Nobili, V. et al. Aliment Pharmocol Ther.2006;24(11):1553-1561.

Trial of Lifestyle Modification & Antioxidant Therapy for Pediatric NAFLD

•53 patients followed for 24 months •Diet & increased physical activity counseling plus placebo OR Vit E 600 IU/day & Vit C 500 mg/day

Placebo Baseline

Placebo 2 year

p Vit E + C Baseline

Vit E + C 2 year

p P*

BMI 26.8 23.7 <0.001 24.9 21.2 <0.001 0.4

ALT 63 34 <0.001 71 40 <0.001 0.6

AST 49 34 <0.001 44 32 <0.001 0.6

Chol 156 132 <0.001 167 127 <0.001 0.02

Trig 89 62 <0.001 87 67 <0.001 0.8

Gluc 87 75 <0.001 83 72 <0.001 0.6

NAS 4 2 <0.001 4 2 <0.001 0.06

Nobili V et al. Hepatology 2008;48:119-128.

P*=intergroup p, NAS=NAFLD activity score on liver biopsy



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Antioxidants for Pediatric NAFLD•Vit E (plus Vit C) plus Diet/Exercise or Placebo plus Diet/Exercise 1-2

•No added improvement with Vitamin E & C•Key to improvement in AST/ALT, insulin resistance, steatosis (US) & NAS score (biopsy) was a 10-20% wt loss

1Nobili V et al. Alim Pharmacol Ther 2006;24:1553-612Nobili V et al. Hepatology 2008;48:119-128.

A1 Weight losers (placebo)A2 Weight not losers (placebo)B1 Weight loser (Vit E/C)B2 Weight not loser (Vit E/C)

Effect of Weight Loss on Liver Free Fatty Acid Uptake and Hepatic Insulin Resistance

Design: Thirty-four healthy obese subjects (body mass index, 33.7 ± 8.0 kg/m2)Studied before and after a very-low-calorie diet for 6 weeksHepatic glucose uptake and endogenous glucoseproduction were measured with duringhyperinsulinemic euglycemia and fasting hepatic fatty acid uptakeLiver volume and fat content were measured usingMRS

Viljanen, A. P. M. et al. JCEM; 2009;94:50-55

Effect of Weight Loss on Liver Free Fatty Acid Uptake and Hepatic Insulin Resistance

Results: Subjects lost weight (11.2 ± 2.9 kg; P < 0.0001). Liver volume decreased by 11% (P < 0.002), whichwas partly explained by decreased liver fat content (P< 0.0001)Liver free fatty acid uptake was 26% lower after weight loss (P < 0.003) and correlated with the decrease in liver fat content (r = 0.54; P < 0.03). Hepatic glucose uptake during insulin stimulation was unchanged, but the endogenous glucose production decreased by 40% (P < 0.04), and hepatic insulin resistance by 40% (P < 0.05)

Viljanen, A. P. M. et al. J Clin Endocrinol Metab 2009;94:50-55Copyright ©2009 The Endocrine Society

Viljanen, A. P. M. et al. J Clin Endocrinol Metab 2009;94:50-55

Effects of Weight Loss on Liver Metabolism

Pharmacological Interventions in NASH

Weight-loss agents (orlistat)Vitamin C and EHepatoprotective agents (ursodeoxycholic acid)Lipid-lowering agents

StatinsFibrates

Insulin-sensitizing AgentsMetforminTZDsExentatide? Vitamin D?




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Mechanism of Metformin

BiguanideReduces hepatic glucose productionIncreases insulin sensitivity in patients with T2DM

Proven to be safe in children and adolescentsUsed in children with T2DM and PCOS

Metformin: Pediatric Trials

Open-label phase 2 clinical trial in non-diabetic children and adolescents with biopsy proven NASH

10 obese children with mean BMI 30.4 kg/m2

treated with metformin 500 mg BID for 24 weeksALT improved from 184 to 98 U/L, p<0.01Liver fat by MRS improved 30 to 23% p<0.01

Schwimmer JB Aliment Pharmacol Ther 2005;21:871-879

Metformin in Pediatric NAFLDOpen label 24 month observational pilot study 500 mg MET TID compared to control group (lifestyle modification)

57 subjects 9-18 yr olds with biopsy proven NAFLD

Metformin not more effective than lifestyle modification alone (both groups improved)

Nobili V et al. Clin Ther 2008;30:1168-76.

Metformin in Pediatric NAFLD

50 adolescents, 6 monthslifestyle modification plus placebo lifestyle modification plus metformin 850mg BID

ALT, GGT, fasting insulin improved in both groupsMetformin group superior:

Fatty liver prevalence & severity (US only),Fasting insulin

Nadeau KJ et al. Pediatric Diabetes 2009;10:5-13.


Mechanism of Thiazolidinediones

Increase insulin sensitivity = increase lipid storageDecrease lipolysis and FFA outputIncrease number of metabolically active adipocytesIncrease adiponectinDecrease leptin, TNF-alpha secretion, and other cytokines



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UTHSCSA study on TZD55 adult pts randomly assigned to hypocaloricdiet with/without pioglitazonePerformed biopsy, MRS, OGTT

Improved glycemic controlImproved ALTDecreased hepatic contentNo change in fibrosis

Safety of TZDs in children not establishedOngoing trial of rosiglizatone in the T2DM TODAY trial

Belfort, R. et al. NEJM. 2006;355:2297-307.

Must Weigh Risks and Benefits

Benefits Risks- Adiponectin

- Hepatic insulin sensitivity

- Steatosis

- Necro-inflammation

- Cardiovascular risk

- Triglycerides w/avandia

- Bone Loss/Fracture

- Weight gain, peripheral fat

- Worsening of CHF

Incretins and Fatty Liver

Incretins are gastrointestinal hormones that enhance the postprandial insulin response. A synthetic form of exendin-4, exenatide, has been developed and undergone extensive clinical trialsExenatide is currently FDA approved for adults and children older than age 16 for treatment of T2DM in combination with sulfonylureas, metformin and/or thioglitazones

Incretins and Fatty LiverExenatide mechanism of action includes:

stimulates glucose-dependent pancreatic insulin secretion restores the first-phase insulin response (often lost in T2DM) suppresses glucagon secretion during periods of hyperglycemia decreases gastric emptying increases satiety

These effects lead to overall decreased insulin resistance and often weight loss

Incretins and Fatty Liver

Recent published outcome data in adults with type 2 diabetes has shown an improvement of ALT while on exenatide

Current study on adults with T2DM and NAFLDTreated for 6 months with intensive insulin therapyFollowed with 6 months of exentatide plus long-acting insulin

Detemir + Exenatide vs. Detemir + Aspart:Effect on Body Weight

80

85

90

95

100

105

Dertemir + Aspart Detemir + EXE

kg

n = 19

//

↓5%p<0.001



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Detemir + Exenatide vs. Detemir + Aspart: Mixed Meal Results

40

90

140

190

240

290

6am

7am

8am

9am

10am

11am

12pm

Time

mg/

dL

Glucose Detemir + Aspart

Glucose Detemir + EXE

INS Detemir + Aspart

INS Detemir + EXE

⁄⁄

n = 19A1c: Pre-tx: 7.0±0.2 vs. Post-tx: 6.8±0.2

p<0.001

Glucose

Insulin

Mean 1st & 2nd Phase Insulin Secretion:Hyperglcemic Clamp

20

40

60

80

100

Mean 1st Phase Mean 2nd Phase

uU/m

L Detemir + AspartDetemir + EXE

⁄⁄

n = 19

↑ 53%p<0.05

↑ 47%p<0.05

Detemir + Exenatide vs. Detemir + Aspart: Effect on Liver Fat

5

6

7

8

9

10

11

Detemir + Aspart Detemir + EXE

% L

FAT

n = 19

↓27%p=0.04

⁄⁄

Vitamin D and Fatty Liver

Vitamin D is found in dietary sources such as fish, eggs, and fortified milk and is increased by sunlight exposure. Frequently found to be deficient in teens who have had suboptimal diets despite sun exposure. Its actions are well-recognized in their role in mineral homeostasis by regulation of calcium absorption from the gut and reabsorption in the kidney. More recently, Vitamin D is associated with autoimmune diseases, cancer, and Type 1 and Type 2 Diabetes.

Vitamin D and Fatty LiverFrom the NHANES III data, cross-sectional analysis was performed on data of 6,228 participants

2,766 non-Hispanic whites, 1,736 non-Hispanic blacks, and 1,726 Mexican Americans

Homeostasis model assessment (HOMA) of IR was inversely associated with serum 25-hydroxyvitamin D (25 OHD) in Mexican Americans (p=0.0024) and non-Hispanic Whites (p=0.058), but not with non-Hispanic Blacks (p=0.93).

BMI was inversely related to 25 OHD levelsNon-Hispanic Whites in the highest quartile of 25 OHD levels had a four-fold lower odds of developing T2DM

Scragg R. et. Al. Diabetes Care. 2004; 27(12):2813-2818.Anastassios G. Pittas. Diabetes Care. 2007;30:980-986

Effects of combined calcium and vitamin D supplementation:

(A) FPG & (B) HOMA-IR



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Vitamin D and Fatty Liver

Cross-sectional analysis of 3577 adolescents from 2001-2004 NHANESMean 25 (OH)D level 24.8 ng/mL

W >MA>AAAssociated with weight and abdominal obesityAdjusting for age, gender, race, and BMI

25 (OH)D inversely associated with plasma glucose concentration

Reis, JP et. Al. Pediatrics. 124: e371-379, 2009

Vitamin D and Fatty LiverIn the cross-sectional analysis of 60 biopsy-proven NAFLD and 60 healthy control patients with comparable age, sex and BMI

NAFLD patients had lower serum 25 (OH)D (51.0 ± 22 vs. 74.5 ±15 nmol/L, p=0.001) when compared to healthy controls An inverse relationship exists between decreasing 25 (OH)D with increasing degree of liver histology (p <0.001) This linear association may suggest a dose-effect relationship

Ongoing trial here at our CHART center to observe if Vitamin D supplementation to physiologic levels has any effect on NAFLD in obese children between the ages of 10 and 17 who present with vitamin D deficiency

Targher G et al. Nut, Met & CV Diseases 17:517-524,2007

Summary

NAFLD is a comorbidity of obesity and diabetesWe do not know the progression of the disease but we do know in adults it can lead to cirrhosis and liver failureWe need to find ways to prevent or stall fatty liver

ReferencesAdams LA, et al. Diagnostic Evaluation of Nonalcoholic Fatty Liver Disease. J ClinGastroenterol. 2006;40:S34-S38.Anastassios G. Pittas. The Effects of Calcium and Vitamin D Supplementation on Blood Glucose and Markers of Inflammation in Nondiabetic Adults. Diabetes Care. 2007; 30:980-986.Belfort, R. et al. A Placebo-Controlled Trial of Pioglitazone in Subjects with Nonalcoholic Steatohepatitis. NEJM. 2006;355:2297-307.Chavez-Tapia NC, et al. Non-alcoholic fatty liver disease in pediatric populations. JPEM. 2007;20:1059-1073.Cusi, Kenneth. Nonalcoholic fatty liver disease in type 2 diabetes mellitus. Current Opinion in Endocrinology, Diabetes & Obesity. 2009, 16:141-149.Larry, L, Pioglitazone trial for NASH: results show promise. Gastroenterology, 2007; 132(3): 836-8.Marchesini, G et al. Obesity-Associated Liver Disease. JCEM. 2008; 93:S74-S80. Nobili, V. et al. Effect of Vitamin E on Aminotransferase Levels and Insulin Resistance in Children With Nonalcoholic Fatty Liver Disease. Aliment PharmocolTher. 2006;24(11):1553-1561.

ReferencesPatton, HM et al. Pediatric Nonalcoholic Fatty Liver Disease: A Critical Appraisal of Current Data and Implications for Future Research. Journal of Pediatric Gastroenterology and Nutrition. 2006;43:413-427.Reis, JP et al. Vitamin D Status and Cardiometabolic Risk Factors in the United States Adolescent Population. 2009;124:e371-379.Schwimmer, JB et al. A phase 2 clinical trial of metformin as a treatment for non-diabetic paediatric non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2005;21:871-879.Scragg R, Sowers M, Bell C. Serum 25-Hydroxyvitamin D, Diabetes, and Ethnicity in the Third National Health and Nutrition Examination Survey. Diabetes Care. 2004; 27(12):2813-2818.Szczepaniak, L. S. et al. Am J Physiol Endocrinol Metab. 2005; 288: E462-E468.Targher G et al. Associations between serum 25-hydroxyvitamin D3 concentrations and liver histology in patients with non-alcoholic fatty liver disease. Nutrition, Metabolism & Cardiovascular Diseases 17:517-524,2007.

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