Cardiovascular Risk Factors and LCH in Adults

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.

Interventions:Cardiovascular 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.

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 1/560.000 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, and/or 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 28:9-14

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Eligibility Criteria:
Inclusion Criteria:

* diagnostic criteria for "definitive diagnosis" of LCH

Exclusion Criteria:

* not participate in strenuous physical activities, on a balanced isocaloric diet for at least 4 weeks prior to the study