Assessment of Changes in Metabolic Activity in Liver & Skeletal Muscle in Patients Suffering From Acromegaly

Acromegaly Clinical Trial

Official title:

Assessment of Changes in Metabolic Activity in Liver & Skeletal Muscle in Patients Suffering From Acromegaly - a 31P/1H Magnetic Resonance Spectroscopy Pilot Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02115906
• Other study ID #: THIGHT_2
• Status: Recruiting
• Phase: Phase 4
• First received: April 11, 2014
• Last updated: September 26, 2016
• Start date: August 2014
• Est. completion date: May 2018

Study information

• Verified date: September 2016
• Source: Medical University of Vienna
• Contact: Peter Wolf, MD
• Phone: 00431404004311
• Email: peter.wolf[@]meduniwien.ac.at
• Is FDA regulated: No
• Health authority: Austria: Federal Office for Safety in Health Care
• Study type: Observational

Clinical Trial Summary

Growth hormone (GH) plays a pivotal role in the regulation of body composition including ectopic lipid deposition in insulin sensitive organs like liver and skeletal muscle. Recent evidence indicates that the GH-IGF1 axis affects body composition via regulating mitochondrial oxidation capacity.

Thus, excessive GH secretion by a pituitary adenoma (Acromegaly) might be accompanied by increased mitochondrial activity leading to inappropriately low intracellular lipid depots, especially in metabolically active tissue like liver and skeletal muscle.

This study aims to assess metabolic activity and intracellular lipid content in skeletal muscle and liver in patients suffering from acromegaly compared to controls by 31P/1H Magnetic resonance spectroscopy before and in follow up examinations 3, 6 and 12 months after initiation of GH lowering treatments including surgery, somatostatinanalogs or pegvisomant, as well as oral glucose tolerance tests at each examination to assess treatment responses and calculate validated parameters for insulin sensitivity and resistance.

Description:

Background: Growth hormone (GH) plays a pivotal role in the regulation of body composition including ectopic lipid deposition in insulin sensitive organs like liver and skeletal muscle. Direct inhibition of growth hormone action by a receptor antagonist has been shown to induce hepatic steatosis and growth hormone replacement decreases liver fat content in obese humans. Of note, recent evidence indicates that the GH-IGF1 axis affects body composition via regulating mitochondrial oxidation capacity.

Hypothesis: Direct and/or indirect effects of GH on mitochondrial function might mediate the changes in body composition and lipid deposition. Thus, excessive GH secretion by a pituitary adenoma (Acromegaly) might be accompanied by increased mitochondrial activity leading to inappropriately low intracellular lipid depots, especially in metabolically active tissue like liver and skeletal muscle.

Aim: Assessment of metabolic activity and intracellular lipid content in skeletal muscle and liver in patients suffering from acromegaly compared to controls.

Methods: Non-interventional study:

• 31P/1H Magnetic resonance spectroscopy before and in follow up examinations 3, 6 and 12 months after initiation of GH lowering treatments including surgery, somatostatinanalogs or pegvisomant.

• oral glucose tolerance tests at each examination to assess treatment responses and calculate validated parameters for insulin sensitivity and resistance.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 24
• Est. completion date: May 2018
• Est. primary completion date: May 2017
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

• age between 18-75 years

Exclusion Criteria:

• (known) overt diabetes mellitus

• known coronary artery disease (history of myocardial infarction or angina pectoris)

• acute or chronic (inflammatory, metabolic [hyperlipidemia, arterial hypertension, thyroid disorder]) disease (healthy controls)

• intake of medication potentially affecting glucose or lipid metabolism

• metal devices or other magnetic material in or on the subjects body which will be hazardous for NMR investigation [heart pacemaker, brain (aneurysm) clip, nerve stimulators, electrodes, ear implants, post coronary by-pass graft (epicardial pace wires), penile implants, colored contact lenses, patch to deliver medications through the skin, coiled spring intrauterine device, vascular filter for blood clots, orthodontic braces, shunt- spinal or ventricular, any metal implants (rods, joints, plates, pins, screws, nails, or clips without MR-authorization), embolization coil, or any metal fragments or shrapnel in the body].

• tendency toward claustrophobia

• severe liver disorders (plasma transaminases elevated > 3fold)

• any acute inflammatory disease within 2 weeks prior the study

• pregnancy

• nursing

• clinically relevant anemia

Study Design

Observational Model: Case Control, Time Perspective: Prospective

Related Conditions & MeSH terms

• Acromegaly

Intervention

Other:
• 1H/31P Magnetic Resonance Spectroscopy
The 31P-MRS examinations will be performed in a 7 T MR system (Siemens Healthcare, Erlangen, Germany) using a double-tuned (31P/1H) surface coil (Rapid Biomedical Ltd, Rimpar, Germany), with a diameter of 10 cm. Participants will be investigated lying in lateral position with the right lobe of the liver positioned over the coil.
• oral glucose tolerance testing
In patients without overt diabetes, glucose tolerance will be assessed by an oral glucose tolerance test, routinely performed at the outpatients clinic. The test will be performed in the morning after an overnight fast of at least 8 hours. Blood will be drawn via a catheter placed in an antecubital vein of one arm. Blood samples for the assessment of glucose, insulin, C-peptide, free fatty acids and growth hormone will be drawn at baseline as well as 30, 60, 90 and 120 minutes after ingestion of 75g glucose in a solution. Concentrations of glucose, insulin and C-peptide will be used to derive parameters of insulin secretion and insulin sensitivity by mathematical modelling.
• Thyroid sonography
In acromegalic patients thyroid morphology will be assessed at the outpatient clinic of the Division of Endocrinology and Metabolism, using standard ultrasound technique. Measurements will be performed by a well- experienced physician at baseline and at each follow up examination in an out-patient care setting.

Locations

Country	Name	City	State
Austria	Medical University Of Vienna, Department of Internal Medicine III	Vienna

Sponsors (1)

Lead Sponsor	Collaborator
Medical University of Vienna

Country where clinical trial is conducted

Austria, 

References & Publications (1)

Valkovic L, Gajdošík M, Traussnigg S, Wolf P, Chmelík M, Kienbacher C, Bogner W, Krebs M, Trauner M, Trattnig S, Krššák M. Application of localized ³¹P MRS saturation transfer at 7 T for measurement of ATP metabolism in the liver: reproducibility and initial clinical application in patients with non-alcoholic fatty liver disease. Eur Radiol. 2014 Jul;24(7):1602-9. doi: 10.1007/s00330-014-3141-x. Epub 2014 Mar 20. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Changes in skeletal muscle energy metabolism	Resting-state ATP turnover will be measured using a ST experiment. The subjects will be lying in a supine position with the surface coil fixed underneath the right calf muscle. Baseline intramyocellular concentrations of phosphorous metabolites will be assessed based on T1 corrected partially relaxed baseline spectra (TR, 15 s; 16 averages). The exchange between ?-ATP and PCr (i.e., CK reaction), and between ?-ATP and Pi (i.e., ATP- synthesis) will be investigated.	before, as well as 3,6,9 and 12 months after initiation of therapy	No
Other	Changes in skeletal muscle lipid content	Intramyocellular lipid content will be assessed using localized single voxel 1H MRS as published by our studygroup[34]. STEAM sequence (VOI= 12x12x12 mm3; TE= 20 ms; TR= 4 sec, NA= 16) data acquisition will be performed in two volumes of interest positioned in soleus and tibialis anterior muscle. Separate spectra without water signal suppression (NA= 4) will be obtained from both muscle groups. Intramyocellular lipid content (IMCL) content will be calculated from ratio of area of methylene (1.25 ppm) to that of water following the individual spin-spin relaxation correction as per cent of tissue water MRS signal.	before, as well as 3,6,9 and 12 months after initiation of therapy	No
Other	Changes in thyroid morphology	In acromegalic patients thyroid morphology will be assessed at the outpatient clinic of the Division of Endocrinology and Metabolism, using standard ultrasound technique. Measurements will be performed by a well- experienced physician at baseline and at each follow up examination in an out-patient care setting.	before and 12 months after initiation of individual therapy	No
Primary	Changes in hepatic energy metabolism	The 31P-MRS examinations will be performed in a 7 T MR system (Siemens Healthcare, Erlangen, Germany) using a double-tuned (31P/1H) surface coil (Rapid Biomedical Ltd, Rimpar, Germany), with a diameter of 10 cm.	before & 3,6,9, and 12 months after initiation of therapy	No
Secondary	Changes in hepatic lipid content	Hepatic lipid content will be assessed using localized single voxel 1H MRS as published by our study group. STEAM sequence (VOI= 3×3×3 cm3; TE= 30, 50, 70, 120 ms; NA= 4 for each TE) data acquisition will be performed during repetitive single breath holds. Hepatocellular lipid (HCL) content will be calculated from ration of summed area of methylene and methyl resonance to that of water following the individual spin-spin relaxation correction as per cent of total tissue MRS signal (water + methylene + methyl).	before, as well as 3,6,9 &12 months after initiation of therapy	No