leptin and Obesity-Hypoventilation-Syndrome

Obesity hypoventilation syndrome (OHS) is defined as daytime hypercapnia in obese individuals in the absence of other underlying causes. In the United States, OHS is present in 10%-20% of obese patients with obstructive sleep apnea and is linked to hypoventilation during sleep. OHS leads to high cardiorespiratory morbidity and mortality, and there is no effective pharmacotherapy. The depressed hypercapnic ventilatory response plays a key role in OHS. The pathogenesis of OHS has been linked to resistance to an adipocyte-produced hormone, leptin, a major regulator of metabolism and control of breathing. Mechanisms by which leptin modulates the control of breathing are potential targets for novel therapeutic strategies in OHS. Recent advances shed light on the molecular pathways related to the central chemoreceptor function in health and disease. Leptin signaling in the nucleus of the solitary tract, retrotrapezoid nucleus, hypoglossal nucleus, and dorsomedial hypothalamus, and anatomical projections from these nuclei to the respiratory control centers, may contribute to OHS. In this review, we describe current views on leptin-mediated mechanisms that regulate breathing and CO2 homeostasis with a focus on potential therapeutics for the treatment of OHS.

Topics: Humans; Hypercapnia; Hypoventilation; Leptin; Obesity; Obesity Hypoventilation Syndrome

To summarize recent primary publications and discuss the impact these finding have on current understanding on the development of hypoventilation in obesity hypoventilation syndrome (OHS), also known as Pickwickian syndrome.. As a result of the significant morbidity and mortality associated with OHS, evidence is building for pre-OHS intermediate states that can be identified earlier and treated sooner, with the goal of modifying disease course. Findings of alterations in respiratory mechanics with obesity remain unchanged; however, elevated metabolism and CO2 production may be instrumental in OHS-related hypercapnia. Ongoing positive airway pressure trials continue to demonstrate that correction of nocturnal obstructive sleep apnea and hypoventilation improves diurnal respiratory physiology, metabolic profiles, quality of life, and morbidity/mortality. Finally, CNS effects of leptin on respiratory mechanics and chemoreceptor sensitivity are becoming better understood; however, characterization remains incomplete.. OHS is a complex multiorgan system disease process that appears to be driven by adaptive changes in respiratory physiology and compensatory changes in metabolic processes, both of which are ultimately counter-productive. The diurnal hypercapnia and hypoxia induce pathologic effects that further worsen sleep-related breathing, resulting in a slowly progressive worsening of disease. In addition, leptin resistance in obesity and OHS likely contributes to blunting of ventilatory drive and inadequate chemoreceptor response to hypercarbia and hypoxemia.

Topics: Animals; Humans; Hypoxia; Leptin; Metabolic Syndrome; Obesity Hypoventilation Syndrome; Quality of Life; Sleep Apnea, Obstructive

The overlap syndrome of obstructive sleep apnoea (OSA) and chronic obstructive pulmonary disease (COPD), in addition to obesity hypoventilation syndrome, represents growing health concerns, owing to the worldwide COPD and obesity epidemics and related co-morbidities. These disorders constitute the end points of a spectrum with distinct yet interrelated mechanisms that lead to a considerable health burden. The coexistence OSA and COPD seems to occur by chance, but the combination can contribute to worsened symptoms and oxygen desaturation at night, leading to disrupted sleep architecture and decreased sleep quality. Alveolar hypoventilation, ventilation-perfusion mismatch and intermittent hypercapnic events resulting from apneas and hypopneas contribute to the final clinical picture, which is quite different from the "usual" COPD. Obesity hypoventilation has emerged as a relatively common cause of chronic hypercapnic respiratory failure. Its pathophysiology results from complex interactions, among which are respiratory mechanics, ventilatory control, sleep-disordered breathing and neurohormonal disturbances, such as leptin resistance, each of which contributes to varying degrees in individual patients to the development of obesity hypoventilation. This respiratory embarrassment takes place when compensatory mechanisms like increased drive cannot be maintained or become overwhelmed. Although a unifying concept for the pathogenesis of both disorders is lacking, it seems that these patients are in a vicious cycle. This review outlines the major pathophysiological mechanisms believed to contribute to the development of these specific clinical entities. Knowledge of shared mechanisms in the overlap syndrome and obesity hypoventilation may help to identify these patients and guide therapy.

Topics: Body Mass Index; Cardiovascular System; Comorbidity; Humans; Leptin; Obesity Hypoventilation Syndrome; Pulmonary Disease, Chronic Obstructive; Pulmonary Ventilation; Respiratory Mechanics; Sleep; Sleep Apnea, Obstructive; Smoking

The obesity-hypoventilation syndrome (OHS), or alveolar hypoventilation in the obese, has been described initially as the "Pickwickian syndrome". It is defined as chronic alveolar hypoventilation (PaO2<70 mmHg, PaCO2 > or =45 mmHg) in obese patients (body mass index>30 kg/m2) who have no other respiratory disease explaining the hypoxemia-hypercapnia.. The large majority of obese subjects are not hypercapnic, even in case of severe obesity (>40 kg/m2). There are three principal causes, which can be associated, explaining alveolar hypoventilation in obese subjects: high cost of respiration and weakness of the respiratory muscles (probably the major cause), dysfunction of the respiratory centers with diminished chemosensitivity, long-term effects of the repeated episodes of obstructive sleep apneas observed in some patients. The role of leptin (hormone produced by adipocytes) in the pathogenesis of this syndrome, has been recently advocated. OHS is generally observed in subjects over 50 years. Its prevalence has markedly increased in recent years, probably due to the present "epidemic" of obesity. The diagnosis is often made after an episode of severe respiratory failure. Comorbidities, favored by obesity, are very frequent: systemic hypertension, left heart diseases, diabetes.. OHS must be distinguished from obstructive sleep apnea syndrome (OSAS) even if the two conditions are often associated. OSAS may be absent in certain patients with OHS (20% of the patients in our experience). On the other hand obesity may be absent in certain patients with OSAS.. Losing weight is the "ideal" treatment of OHS but in fact it cannot be obtained in most patients. Nocturnal ventilation (continuous positive airway pressure and mainly bilevel non invasive ventilation) is presently the best treatment of OHS and excellent short and long-term results on symptoms and arterial blood gases have been recently reported.

Topics: Age Factors; Chemoreceptor Cells; Diagnosis, Differential; Humans; Leptin; Obesity Hypoventilation Syndrome; Respiratory Muscles; Respiratory Therapy; Sleep Apnea, Obstructive; Work of Breathing

The prevalence of obesity has considerably increased during the past thirty years. Possible consequences of obesity on respiratory physiology include a restrictive disorder, changes in ventilatory mechanics and an alteration of respiratory drive. Apart from the well established relation between obesity and obstructive sleep apnea-hypopnea syndrome, obesity is associated with two other respiratory disorders. On one hand, epidemiological and animal data suggest a causal relationship between obesity and asthma. On the other hand, morbid obesity is associated, through an alteration of the respiratory drive involving leptin, with a diurnal and nocturnal alveolar hypoventilation defining the obesity-hypoventilation syndrome. These data emphasize the necessity for the medical practitioner to investigate any respiratory symptomatology in obese patients.

Topics: Animals; Asthma; Body Mass Index; Humans; Leptin; Obesity; Obesity Hypoventilation Syndrome; Prevalence; Respiratory Tract Diseases; Sleep Apnea, Obstructive; Switzerland

Obesity hypoventilation syndrome (OHS) consists of a combination of obesity and chronic hypercapnia accompanied by sleep-disordered breathing. During the last 3 decades, the prevalence of extreme obesity has markedly increased in the United States and other countries. With a global epidemic of obesity, the prevalence of OHS is bound to increase. Patients with OHS have a lower quality of life with increased health-care expenses and are at a higher risk for the development of pulmonary hypertension and early mortality compared to eucapnic patients with sleep-disordered breathing. Despite the significant morbidity and mortality associated with this syndrome, it is often unrecognized and treatment is frequently delayed. Clinicians must maintain a high index of suspicion since early recognition and treatment reduces the high burden of morbidity and mortality associated with this syndrome. In this review, we will discuss the definition and clinical presentation of OHS, provide a summary of its prevalence, review the current understanding of the pathophysiology, and discuss the recent advances in the therapeutic options.

Topics: Acetazolamide; Algorithms; Animals; Bariatric Surgery; Comorbidity; Continuous Positive Airway Pressure; Contraceptives, Oral, Synthetic; Diuretics; Humans; Hypercapnia; Leptin; Medroxyprogesterone; Obesity Hypoventilation Syndrome; Positive-Pressure Respiration; Quality of Life; Respiratory Muscles; Tracheostomy; Treatment Outcome

Long-term nocturnal non-invasive mechanical ventilation (NIMV) is an effective treatment for obesity-hypoventilation syndrome (OHS), improving central carbon dioxide (CO(2)) sensitivity. Leptin might contribute to sustain adequate ventilation in obesity. The aim of the study was to investigate the role of leptin in the OHS pathogenesis looking at its relationship to CO(2) sensitivity before and after NIMV in OHS patients.. In six obese patients (3F/3M; aged 63+/-9 yr; BMI 47.0+/-4.5 kg/m(2)) with OHS and without obstructive sleep apnoea-hypopnoea (OSAH) diurnal arterial blood gases, fasting plasma leptin concentration and CO(2) chemosensitivity were determined before and after 10.3+/-5.6 (range 6-20) months of NIMV.. After NIMV improvements were observed in gas exchange (PaO(2) from 51.3+/-6.7 to 75.0+/-10.3 mmHg, p<0.01; PaCO(2) from 55.5+/-4.8 to 43.7+/-1.2 mmHg, p<0.01; [HCO(3)(-)] from 33.3+/-3.8 to 29.8+/-1.7 mmol/l, p<0.05) and CO(2) chemosensitivity, measured as P(0.1)/PetCO(2) slope (from 0.09+/-0.07 to 0.18+/-0.07 cmH(2)O/mmHg, p<0.05) and V(E)/PetCO(2) slope (from 0.4+/-0.3 to 0.9+/-0.5l/min/mmHg, p=0.07). Plasma leptin increased from 34.5+/-21.1 ng/ml to 50.2+/-22.9 ng/ml (p<0.01) after NIMV and changes of the P(0.1)/PetCO(2) slope correlated with percent changes of plasma leptin (r(2)=0.79, p<0.05).. These findings suggest a possible role of leptin in the recovery of neuromuscular response to hypercapnia obtained during long-term nocturnal NIMV in OHS patients without OSAH.

Topics: Aged; Anthropometry; Carbon Dioxide; Circadian Rhythm; Fasting; Female; Follow-Up Studies; Humans; Hypercapnia; Leptin; Male; Middle Aged; Obesity Hypoventilation Syndrome; Oxygen; Partial Pressure; Pilot Projects; Pulmonary Gas Exchange; Respiration, Artificial