Dynamic Post-Prandial Metabolism in Patients With Non-Alcoholic Fatty Liver Disease
Dynamic Post-Prandial Metabolism in Patients With Non-Alcoholic Fatty Liver Disease
Background:

 Metabolism refers to the many chemical pathways by which various compounds, including food,
 are processed and used in the body. People with non-alcoholic fatty liver disease (NAFLD)
 have too much fat in their liver cells, but what causes it is unclear. One explanation is
 that people with NAFLD process food and metabolize it differently than people without NAFLD.
 Researchers want to compare how food is metabolized in people with and without NAFLD.

 Objective:

 To better understand how food intake influences the development and progression of NAFLD.

 Eligibility:

 People ages 18 and older with NAFLD or with a non-NAFLD metabolic syndrome

 Healthy volunteers ages 18 and older

 Design:

 Participants will be screened with medical history, surveys, physical exam, and blood tests.
 This will have ultrasound of the abdomen. This uses sound waves to image internal organs.

 Participants will stay at the Clinical Center for 2 nights.

 They will fast he first night.

 On the second day they will:

 Have their metabolism monitored in a metabolism research room for 24 hours

 Have a catheter inserted into an arm vein for several blood tests

 Drink an Ensure Plus for breakfast

 Have solid meals for lunch and dinner

 Have several urine tests.

 The final morning, they will:

 Have more blood tests.

 Have a DXA test to measure the fat in the body. They will lie on their backs for 15-25
 minutes while an x-ray machine is positioned over areas of the body.

 ...
Non-alcoholic fatty liver disease (NAFLD) is the most common hepatic disorder in the Western
 world, and is a leading cause of liver-related morbidity and mortality. Excessive caloric
 intake and specific nutritional components have been implicated in its pathogenesis, but the
 complex metabolic pathways linking nutrient consumption with hepatic fat accumulation have
 not yet been fully elucidated. Analysis of pathophysiology and the search for biomarkers in
 NAFLD has largely focused on fasting samples; the dynamic response to a caloric load has not
 been interrogated, beyond glucose tolerance testing. Metabolomics is a novel high-throughput
 technique, allowing for simultaneous detection of hundreds to thousands of metabolites, and
 the evaluation of their interconnectivity and causal relationships. We propose a pilot study
 to investigate the metabolic response of patients with NAFLD to a standardized food
 challenge, by applying a metabolomics-based dynamic approach. In this study we will recruit
 up to 50 patients with NAFLD and compare them to 12 controls with metabolic syndrome without
 NAFLD, and 12 healthy controls. Following an overnight fast, subjects will be situated in a
 metabolic chamber for continuous measurement of metabolic rates, and will be given a liquid
 mixed meal containing approximately 30% of daily caloric requirement over a period of 15
 minutes. The energy expenditure (EE) and respiratory quotient (RQ), reflecting preference for
 carbohydrate or fat oxidation, will be measured at 1-minute resolution. Blood will be drawn
 at baseline, and at 30 min, 1, 2, 4 and 24 hours after ingestion. Plasma will be separated
 and stored in -80 (Infinite)C. Following completion of recruitment, stored samples will be
 analyzed at the NCI Laboratory of Metabolism by LC/MS and GC/MS, metabolites of interest
 identified, and individual metabolites quantitated and normalized to their pre-prandial
 level. Study results will hopefully identify novel metabolic markers of disease, and uncover
 altered signaling pathways unique to NAFLD that are activated primarily under fed state
 conditions.
-  INCLUSION CRITERIA:

 For the entire cohort:

 -  Male or female aged > 18 years

 -  Ability to provide informed consent

 For group 1 subjects (NAFLD)

 -  Biopsy-proven NAFLD within 2 years prior to screening, OR

 -  The presence of at least two of the following criteria:

 -  Suggestion of liver fat by an imaging study (ultrasound, CT scan, MRI or MR
 spectroscopy) performed in the 6 months prior to screening

 -  Elevated aminotransferase levels (ALT > 31 U/L for men or > 19 U/L for women, or AST >
 30 U/L) on at least two occasions in the 6 months preceding enrollment.

 -  Presence of the metabolic syndrome, defined according to the modified AHA/NCEP
 criteria as the presence of at least three of:

 i. Abdominal obesity, defined as waist circumference > 102 cm for men or > 88 cm for
 women

 ii. Elevated triglycerides (> 150 mg/dL) or the use of medication to lower triglycerides

 iii. Reduced HDL cholesterol (< 40 mg/DL for men or < 50 mg/dL for women)

 iv. Elevated blood pressure (> 135/80 mmHg) or use of medication for hypertension

 v. Elevated fasting glucose levels (> 100 mg/dL) or use of anti-diabetic medication

 For the purpose of inclusion, the presence of overt diabetes mellitus type 2 will be
 considered equivalent to the presence of the metabolic syndrome, even if the other criteria
 are absent.

 For group 2 subjects (non-NAFLD metabolic syndrome):

 -  Evidence of metabolic syndrome

 -  Normal transaminases (ALT less than or equal to 31 U/L for men or less than or equal
 to 19 U/L for women, or AST less than or equal to 30 U/L) at screening

 -  Absence of liver fat by imaging or liver biopsy within 6 months of screening

 For group 3 subjects (healthy volunteers):

 -  No history of known liver disease

 -  Not on any regular systemic medications (with the exception of oral contraceptives)

 -  BMI <= 25 kg/m2

 -  Non diabetic

 -  Normal transaminases and fasting glucose (<95 mg/dL)

 EXCLUSION CRITERIA:

 1. Concomitant liver disease such as autoimmune hepatitis, primary biliary cirrhosis,
 primary sclerosing cholangitis, Wilson s disease, alpha-1 antitrypsin deficiency

 2. Chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV). Patients
 who were treated successfully for HCV and achieved sustained virological response can
 be eligible for enrollment > 18 months after treatment cessation. Patients receiving
 antiviral therapy are ineligible.

 3. Estimated average alcohol consumption > 30 g/d for men or > 20 g/d for women in the 6
 months prior to enrollment, or binge-drinking behavior .

 4. Gain or loss of > 10% body weight within the 6 months prior to enrollment.

 5. Decompensated liver cirrhosis, defined as a past or present occurrence of a
 decompensation event (variceal bleeding, ascites, spontaneous bacterial peritonitis,
 encephalopathy or hepatocellular carcinoma or by albumin < 3 g/dl, PT > 3 seconds
 above the upper limit of the norm, platelet count < 70,000 or total bilirubin > 2
 mg/dL (in the absence of Gilbert s syndrome).

 6. Pregnancy or lactation

 7. Treatment with medications known to cause fatty liver disease such as atypical
 neuroleptics, tetracycline, methotrexate or tamoxifen

 8. Disorders interfering with substrate absorption such as gastric bypass surgery,
 malabsorption disorders, use of orlistat or bile acid sequestrants, or extensive small
 bowel resection.

 9. Diabetic patients requiring insulin treatment

 10. Lactose intolerance or allergy to Ensure or one or more of its components

 11. Hyper/hypothyroidism

 12. Inability to remain sedentary for 4 hours, or to remain for 26-30 hours in the
 metabolic chamber

 13. Inability to obtain vascular access for the required blood samples