Ignite Creation Date:
2024-05-05 @ 5:33 PM
Last Modification Date:
2024-10-26 @ 9:33 AM
Study NCT ID:
NCT00483925
Status:
UNKNOWN
Last Update Posted:
2007-06-08
First Post:
2007-06-06
Brief Title:
Cardiovascular Risk Factors and LCH in Adults
Sponsor:
Laikο General Hospital Athens
Organization:
Laikο General Hospital Athens
Study Overview
Official Title:
CARDIOVASCULAR RISK FACTORS IN ADULT PATIENTS WITH MULTISYSTEM LANGERHANS-CELL HISTIOCYTOSIS EVIDENCE OF GLUCOSE METABOLISM ABNORMALITIES
Status:
UNKNOWN
Status Verified Date:
2007-06
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Langerhans-cell histiocytosis LCH is a rare disease with features of chronic inflammation and hypopituitarism conditions associated with increased risk of cardiovascular diseases
Objective To investigate glucose and lipid metabolism insulin resistance structural arterial and functional endothelial properties in patients with multisystem LCH in a prospective observational study
InterventionsCardiovascular risk factors arterial blood pressure lipid profile mathematical indices of insulin resistance IR intima media thickness brachial artery flow mediated dilatation dynamic indices of IR pituitary function and C-reactive protein will be estimated in patients with LCH and in a control group matched for gender age BMI and smoking habits
Objective To investigate glucose and lipid metabolism insulin resistance structural arterial and functional endothelial properties in patients with multisystem LCH in a prospective observational study
InterventionsCardiovascular risk factors arterial blood pressure lipid profile mathematical indices of insulin resistance IR intima media thickness brachial artery flow mediated dilatation dynamic indices of IR pituitary function and C-reactive protein will be estimated in patients with LCH and in a control group matched for gender age BMI and smoking habits
Detailed Description:
CARDIOVASCULAR RISK FACTORS IN ADULT PATIENTS WITH MULTISYSTEM LANGERHANS-CELL HISTIOCYTOSIS EVIDENCE OF ABNORMALITIES OF CARBOHYDRATE METABOLISM
Langerhans cell histiocytosis LCH is a rare disease usually affecting children although it has recently increasingly been recognized in adults with a prevalence of approximately 1560000 cases LCH is characterized by the aberrant proliferation of dendritic cells of the monocyte-macrophage system that resemble normal epidermal Langerhans cells These cells can infiltrate many sites of the body leading to either localized lesions or widespread systemic disease Although LCH has been shown to be a clonal disorder it also exhibits features of an inflammatory disease as altered expression of cytokines and cellular adhesion molecules important for the migration and homing of Langerhans cell has been documented In addition LCH shows a particular predilection for hypothalamo-pituitary axis HPA involvement leading to diabetes insipidus and or anterior pituitary dysfunction in 15-50 and 5-20 of patients respectively 3 These percentages may be higher in adult patients with multisystem involvement being 94 and 59 respectively
The ongoing inflammatory process and the presence of hypopituitarism are considered to be two independent risk factors for cardiovascular diseases probably through the induction of insulin resistance IR The various therapies used for the treatment of multisystem LCH chemotherapy radiotherapy and particularly glucocorticoids may also adversely affect the cardiovascular system mostly through IR It is therefore possible that patients with LCH represent a group at higher risk for cardiovascular diseases through the additive effect of a number of different contributing mechanisms known to induce IR Insulin resistance besides producing an adverse metabolic profile can also lead to endothelial dysfunction and early vascular disease Early vascular disease can be detected by non-invasive surrogate markers such as intima-media thickness IMT for vascular structure properties and flow-mediated vasodilatation FMD for vascular functional properties Carotid IMT is considered an established marker for early atherosclerotic disease and predictor of future cardiovascular events 16 whereas brachial artery FMD has been correlated with coronary endothelial function a well-known predictor of future cardiovascular events 18
Main outcome measures Cardiovascular risk factors assessment were estimated in patients with LCH and compared to controls the effect of hypopituitarism disease activity and or treatment were determined
SUBJECTS AND METHODS All patients have to fulfil the diagnostic criteria for definitive diagnosis of LCH Matched to sex age and BMI healthy individuals in good health and not receiving any medication known to affect carbohydrate sex hormone metabolism andor endothelial function for at least 3 months prior have also to be recruited for the study
Clinical data of the patients as well as hormonal and imaging assessment will be registered
All subjects do not have participate in strenuous physical activities and have to be on a balanced isocaloric diet for at least 4 weeks prior to the study Current smokers will be asked not to smoke one day before the hemodynamic study
Cardiovascular risk factors assessment
Clinical cardiovascular risk
BMI
waist circumference
systolic SBP and diastolic DBP blood pressure Metabolic Profile
The metabolic study of all patients will be performed after a 10h overnight fasting
Oral glucose tolerance test
Glucose insulin
Total cholesterol HDL-cholesterol triglycerides
Indices of Insulin resistance GIR HOMA QUICKI MATSUDA glucose and insulin response to glucose by calculating the area under the curve AUC during the OGTT performance for glucose AUCGLU and insulin AUCINS using the trapezoidal rule predicted index of first phase of insulin secretion predicted index of second phase of insulin secretion
Hemodynamic studies
The hemodynamic study will be performed the day after the metabolic study Both functional and structural arterial properties will be assessed by non-invasive easily reproducible hemodynamic ultrasonographic methods namely IMT measurement in carotid arteries and both endothelium-dependent FMD and endothelium-independent nitrate-induced dilatation NID measurement in brachial artery IMT FMD and NID were measured by B-Mode high-resolution ultrasound imaging VIVID PRO GENERAL ELECTRIC
Arterial stiffness will be assessed by Applanation Tonometry SphygmocorTM PWV MEDICAL on radial artery
Inflammatory index C-reactive protein CRP measurement References Baumgartner I von Hochstetter A Baumert B Luetolf U Follath F 1997 Med Pediatr Oncol 289-14
Dunger DB Broadbent V Yeoman E Seckl JR Lightman SL Grant DB Pritchard J 1989 The frequency and natural history of diabetes insipidus in children with Langerhans-cell histiocytosis N Engl J Med 3211157-1162
Willman CL Busque L Griffith BB Favara BE McClain KL Duncan MH Gilliland DG 1994 Langerhans-cell histiocytosis histiocytosis X--a clonal proliferative disease N Engl J Med 331154-160
de Graaf JH Tamminga RY Dam-Meiring A Kamps WA Timens W 1996 The presence of cytokines in Langerhans cell histiocytosis J Pathol 180400-40
Egeler RM Favara BE van Meurs M Laman JD Claassen E 1999 Differential In situ cytokine profiles of Langerhans-like cells and T cells in Langerhans cell histiocytosis abundant expression of cytokines relevant to disease and treatment Blood 944195-4201
Malpas JS 1998 Langerhans cell histiocytosis in adults Hematol Oncol Clin North Am 12259-26
Willis B Ablin A Weinberg V Zoger S Wara WM Matthay KK 1996 Disease course and late sequelae of Langerhans cell histiocytosis 25-year experience at the University of California San Francisco J Clin Oncol 142073-2082
Grois NG Favara BE Mostbeck GH Prayer D 1998 Central nervous system disease in Langerhans cell histiocytosis Hematol Oncol Clin North Am 12287-305
Makras P Samara C Antoniou M Zetos A Papadogias D Nikolakopoulou Z Andreakos E Toloumis G Kontogeorgos G Piaditis G Kaltsas GA 2006 Evolving radiological features of hypothalamo-pituitary lesions in adult patients with Langerhans cell histiocytosis LCH Neuroradiology 4837-44
Alexander RW 1994 Inflammation and coronary artery disease N Engl J Med 1994 Aug 183317468-9
Rosen T Bengtsson BA 1990 Premature mortality due to cardiovascular disease in hypopituitarism Lancet 336285-288
Wilson PW Kannel WB Silbershatz H DAgostino RB 1999 Clustering of metabolic factors and coronary heart disease Arch Intern Med 1591104-1109
Wei L MacDonald TM Walker BR 2004 Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease Ann Intern Med 141764-770
Andrews RC Walker BR 1999 Glucocorticoids and insulin resistance old hormones new targets Clin Sci Lond 96513-523
W Wheatcroft SB Williams IL Shah AM Kearney MT 2003 Pathophysiological implications of insulin resistance on vascular endothelial function Diabet Med 20255-268
Hodis HN Mack WJ LaBree L Selzer RH Liu CR Liu CH Azen SP 1998 The role of carotid arterial intima-media thickness in predicting clinical coronary events
Ann Intern Med 128262-269
Schachinger V Britten MB Zeiher AM 2000 Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease
Circulation 1011899-1906
Anderson TJ Uehata A Gerhard MD Meredith IT Knab S Delagrange D Lieberman EH Ganz P Creager MA Yeung AC et al 1995 Close relation of endothelial function in the human coronary and peripheral circulations J Am Coll Cardiol 261235-1241
Arico M Girschikofsky M Genereau T Klersy C McClain K Grois N Emile JF Lukina E De Juli E Danesino C 2003 Langerhans cell histiocytosis in adults Report from the International Registry of the Histiocyte Society Eur J Cancer 392341-2348
Legro RS Finegood D Dunaif A 1998 A fasting glucose to insulin ratio is a useful measure of insulin sensitivity in women with polycystic ovary syndrome J Clin Endocrinol Metab 832694-2698
Bergman RN Prager R Volund A Olefsky JM 1987 Equivalence of the insulin sensitivity index in man derived by the minimal model method and the euglycemic glucose clamp J Clin Invest 79790-800
Katz A Nambi SS Mather K Baron AD Follmann DA Sullivan G Quon MJ 2000 Quantitative insulin sensitivity check index a simple accurate method for assessing insulin sensitivity in humans J Clin Endocrinol Metab 852402-2410
Matsuda M DeFronzo RA 1999 Insulin sensitivity indices obtained from oral glucose tolerance testing Comparison with the euglycemic insulin clamp Diabetes Care 221462-1470
Stumvoll M Mitrakou A Pimenta W Jenssen T Yki-Jarvinen H Van Haeften T Renn W Gerich J Use of the oral glucose tolerance test to assess insulin release and insulin sensitivity Diabetes Care 295-301
Alexandraki K Protogerou A Papaioannou TG Piperi C Mastorakos G Lekakis J Panidis D Diamanti-Kandarakis E 2006 Early Microvascular and Macrovascular Dysfunction is not Accompanied by Structural Injury in Polycystic Ovary Syndrome HORMONES Athens Greece 5126-136
Langerhans cell histiocytosis LCH is a rare disease usually affecting children although it has recently increasingly been recognized in adults with a prevalence of approximately 1560000 cases LCH is characterized by the aberrant proliferation of dendritic cells of the monocyte-macrophage system that resemble normal epidermal Langerhans cells These cells can infiltrate many sites of the body leading to either localized lesions or widespread systemic disease Although LCH has been shown to be a clonal disorder it also exhibits features of an inflammatory disease as altered expression of cytokines and cellular adhesion molecules important for the migration and homing of Langerhans cell has been documented In addition LCH shows a particular predilection for hypothalamo-pituitary axis HPA involvement leading to diabetes insipidus and or anterior pituitary dysfunction in 15-50 and 5-20 of patients respectively 3 These percentages may be higher in adult patients with multisystem involvement being 94 and 59 respectively
The ongoing inflammatory process and the presence of hypopituitarism are considered to be two independent risk factors for cardiovascular diseases probably through the induction of insulin resistance IR The various therapies used for the treatment of multisystem LCH chemotherapy radiotherapy and particularly glucocorticoids may also adversely affect the cardiovascular system mostly through IR It is therefore possible that patients with LCH represent a group at higher risk for cardiovascular diseases through the additive effect of a number of different contributing mechanisms known to induce IR Insulin resistance besides producing an adverse metabolic profile can also lead to endothelial dysfunction and early vascular disease Early vascular disease can be detected by non-invasive surrogate markers such as intima-media thickness IMT for vascular structure properties and flow-mediated vasodilatation FMD for vascular functional properties Carotid IMT is considered an established marker for early atherosclerotic disease and predictor of future cardiovascular events 16 whereas brachial artery FMD has been correlated with coronary endothelial function a well-known predictor of future cardiovascular events 18
Main outcome measures Cardiovascular risk factors assessment were estimated in patients with LCH and compared to controls the effect of hypopituitarism disease activity and or treatment were determined
SUBJECTS AND METHODS All patients have to fulfil the diagnostic criteria for definitive diagnosis of LCH Matched to sex age and BMI healthy individuals in good health and not receiving any medication known to affect carbohydrate sex hormone metabolism andor endothelial function for at least 3 months prior have also to be recruited for the study
Clinical data of the patients as well as hormonal and imaging assessment will be registered
All subjects do not have participate in strenuous physical activities and have to be on a balanced isocaloric diet for at least 4 weeks prior to the study Current smokers will be asked not to smoke one day before the hemodynamic study
Cardiovascular risk factors assessment
Clinical cardiovascular risk
BMI
waist circumference
systolic SBP and diastolic DBP blood pressure Metabolic Profile
The metabolic study of all patients will be performed after a 10h overnight fasting
Oral glucose tolerance test
Glucose insulin
Total cholesterol HDL-cholesterol triglycerides
Indices of Insulin resistance GIR HOMA QUICKI MATSUDA glucose and insulin response to glucose by calculating the area under the curve AUC during the OGTT performance for glucose AUCGLU and insulin AUCINS using the trapezoidal rule predicted index of first phase of insulin secretion predicted index of second phase of insulin secretion
Hemodynamic studies
The hemodynamic study will be performed the day after the metabolic study Both functional and structural arterial properties will be assessed by non-invasive easily reproducible hemodynamic ultrasonographic methods namely IMT measurement in carotid arteries and both endothelium-dependent FMD and endothelium-independent nitrate-induced dilatation NID measurement in brachial artery IMT FMD and NID were measured by B-Mode high-resolution ultrasound imaging VIVID PRO GENERAL ELECTRIC
Arterial stiffness will be assessed by Applanation Tonometry SphygmocorTM PWV MEDICAL on radial artery
Inflammatory index C-reactive protein CRP measurement References Baumgartner I von Hochstetter A Baumert B Luetolf U Follath F 1997 Med Pediatr Oncol 289-14
Dunger DB Broadbent V Yeoman E Seckl JR Lightman SL Grant DB Pritchard J 1989 The frequency and natural history of diabetes insipidus in children with Langerhans-cell histiocytosis N Engl J Med 3211157-1162
Willman CL Busque L Griffith BB Favara BE McClain KL Duncan MH Gilliland DG 1994 Langerhans-cell histiocytosis histiocytosis X--a clonal proliferative disease N Engl J Med 331154-160
de Graaf JH Tamminga RY Dam-Meiring A Kamps WA Timens W 1996 The presence of cytokines in Langerhans cell histiocytosis J Pathol 180400-40
Egeler RM Favara BE van Meurs M Laman JD Claassen E 1999 Differential In situ cytokine profiles of Langerhans-like cells and T cells in Langerhans cell histiocytosis abundant expression of cytokines relevant to disease and treatment Blood 944195-4201
Malpas JS 1998 Langerhans cell histiocytosis in adults Hematol Oncol Clin North Am 12259-26
Willis B Ablin A Weinberg V Zoger S Wara WM Matthay KK 1996 Disease course and late sequelae of Langerhans cell histiocytosis 25-year experience at the University of California San Francisco J Clin Oncol 142073-2082
Grois NG Favara BE Mostbeck GH Prayer D 1998 Central nervous system disease in Langerhans cell histiocytosis Hematol Oncol Clin North Am 12287-305
Makras P Samara C Antoniou M Zetos A Papadogias D Nikolakopoulou Z Andreakos E Toloumis G Kontogeorgos G Piaditis G Kaltsas GA 2006 Evolving radiological features of hypothalamo-pituitary lesions in adult patients with Langerhans cell histiocytosis LCH Neuroradiology 4837-44
Alexander RW 1994 Inflammation and coronary artery disease N Engl J Med 1994 Aug 183317468-9
Rosen T Bengtsson BA 1990 Premature mortality due to cardiovascular disease in hypopituitarism Lancet 336285-288
Wilson PW Kannel WB Silbershatz H DAgostino RB 1999 Clustering of metabolic factors and coronary heart disease Arch Intern Med 1591104-1109
Wei L MacDonald TM Walker BR 2004 Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease Ann Intern Med 141764-770
Andrews RC Walker BR 1999 Glucocorticoids and insulin resistance old hormones new targets Clin Sci Lond 96513-523
W Wheatcroft SB Williams IL Shah AM Kearney MT 2003 Pathophysiological implications of insulin resistance on vascular endothelial function Diabet Med 20255-268
Hodis HN Mack WJ LaBree L Selzer RH Liu CR Liu CH Azen SP 1998 The role of carotid arterial intima-media thickness in predicting clinical coronary events
Ann Intern Med 128262-269
Schachinger V Britten MB Zeiher AM 2000 Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease
Circulation 1011899-1906
Anderson TJ Uehata A Gerhard MD Meredith IT Knab S Delagrange D Lieberman EH Ganz P Creager MA Yeung AC et al 1995 Close relation of endothelial function in the human coronary and peripheral circulations J Am Coll Cardiol 261235-1241
Arico M Girschikofsky M Genereau T Klersy C McClain K Grois N Emile JF Lukina E De Juli E Danesino C 2003 Langerhans cell histiocytosis in adults Report from the International Registry of the Histiocyte Society Eur J Cancer 392341-2348
Legro RS Finegood D Dunaif A 1998 A fasting glucose to insulin ratio is a useful measure of insulin sensitivity in women with polycystic ovary syndrome J Clin Endocrinol Metab 832694-2698
Bergman RN Prager R Volund A Olefsky JM 1987 Equivalence of the insulin sensitivity index in man derived by the minimal model method and the euglycemic glucose clamp J Clin Invest 79790-800
Katz A Nambi SS Mather K Baron AD Follmann DA Sullivan G Quon MJ 2000 Quantitative insulin sensitivity check index a simple accurate method for assessing insulin sensitivity in humans J Clin Endocrinol Metab 852402-2410
Matsuda M DeFronzo RA 1999 Insulin sensitivity indices obtained from oral glucose tolerance testing Comparison with the euglycemic insulin clamp Diabetes Care 221462-1470
Stumvoll M Mitrakou A Pimenta W Jenssen T Yki-Jarvinen H Van Haeften T Renn W Gerich J Use of the oral glucose tolerance test to assess insulin release and insulin sensitivity Diabetes Care 295-301
Alexandraki K Protogerou A Papaioannou TG Piperi C Mastorakos G Lekakis J Panidis D Diamanti-Kandarakis E 2006 Early Microvascular and Macrovascular Dysfunction is not Accompanied by Structural Injury in Polycystic Ovary Syndrome HORMONES Athens Greece 5126-136
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None