Chronic obstructive lung disease (COPD), a disorder of chronic airflow limitation
not reversed by bronchodilators, is now the third most common cause of death worldwide.
The understanding of COPD has changed considerably over the past decade with the definition
of the disease having moved from a simple airflow limitation-centric view of the disease
to the understanding that COPD is a complex and heterogeneous condition with significant
extrapulmonary manifestations that among others include cardiovascular disease, skeletal
muscle dysfunction, and diabetes. A link between metabolic syndrome (MetS) and COPD
has been observed in several cross-sectional and longitudinal studies, and the syndrome
has been identified as an independent risk factor for worsening respiratory symptoms,
increasing lung function impairment, pulmonary hypertension, and asthma.[1] In this
issue of Lung India, Acharya et al.[2] report that MetS was found in 44%, 46%, and
31% of their COPD patients based on definitions by the NCEP ATP III, modified NCEP
ATP III, and IDF criteria, respectively, against the statistics of 31%, 38%, and 32%,
respectively, among non-COPD controls. These results suggest a trend toward a higher
frequency of MetS in COPD cases.
Several studies have reported a higher risk of MetS in COPD. In a recent meta-analysis
of 19 studies involving 4208 COPD patients, the pooled prevalence of MetS was 34%.
Patients with MetS and COPD had higher body mass index (BMI), had higher forced expiratory
volume in one second (FEV1%) predicted, and were more frequently females compared
to controls.[3] The prevalence of diabetes, a frequent accompaniment of MetS, in various
studies in COPD ranges from 3 to 12%.[4
5] Indian data on the prevalence of MetS or its components in COPD are sparse. Dave
et al. reported MetS in 42% of their patients with COPD compared to 20% among age-matched
controls.[6] In another study from North India,[7] the prevalence of MetS was 27%;
whereas in a yet another study from Himachal Pradesh,[8] MetS was found in 70% of
COPD cases compared to 30% among controls. Ethnicity-based regional differences in
the prevalence of comorbidities in COPD may exist, as in Japanese patients, cardiovascular
disease and MetS syndrome were found to be less prevalent while osteoporosis and malnutrition
were more frequent.[9] Similarly, Korean researchers did not find any association
between COPD and a greater prevalence of diabetes among Korean patients with COPD.[10]
The recognition of MetS as an association of lung disease is rather recent, and several
studies have reported an association between MetS and impairment of lung function.
A large, recent study involving more than 121,000 adult participants showed that MetS
was associated with lower FEV1 or FVC when adjusted for confounding factors such as
smoking, age/sex, education, physical activity, or BMI. The individual components
of MetS, i.e., obesity, dyslipidemia, fasting hyperglycemia, and hypertension were
independently associated with impairment of lung function too,[11] abdominal obesity
having the strongest association.[11] Obesity is associated with a decrease in expiratory
reserve volume and functional, residual capacity due to its extrapulmonary restrictive
component.[12] Obesity can also perpetuate both systemic and pulmonary inflammation
since excessive adipose tissue is able to produce various proinflammatory cytokines
including interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α).[13] There
is a higher expression of inflammatory markers and adipokines such as leptin and adiponectin
3 in visceral fat. Dysregulation of adipokines, through their effects on bronchial
hyperreactivity and effect on airway epithelial cell receptors, is a potential mechanism
for obesity-mediated airway changes in airway disease.[1] Adipokines could also play
a role in MetS-mediated effects in lung function.[1] Leptin may propagate pulmonary
as well as systemic inflammation and together with resistin contribute to the pathogenesis
of related dysglycemia.[14]
Paradoxically, however, low BMI is associated with higher mortality from respiratory
causes.[15] This paradox highlights the unresolved issue of the “obesity paradox”
seen in COPD, where a higher BMI is associated with a decrease in overall mortality.
There have been discrepancies among various studies in this regard which may be a
result of different phenotypes studied (emphysema versus chronic bronchitis predominant)
that by themselves have a different effect on the skeletal muscle mass. Hyperlipidemia
is another cardinal manifestation of the MetS. Fatty acid accumulation leads to potentiated
inflammation that could prove to cause lung function impairment. Circulating levels
of fatty acids are regulated by insulin-stimulated uptake and release of triglycerides
and free fatty acids by adipocytes.[16]
COPD may coexist with obstructive sleep apnea (OSA) (overlap syndrome).[17] Patients
with overlap syndrome have a higher risk of cardiopulmonary disease, and OSA may contribute
to the development of insulin resistance (IR) and hyperglycemia in MetS. Several mechanisms
are believed to contribute to the pathogenesis of OSA-related IR: sleep fragmentation
and intermittent hypoxia,[18] inflammation and oxidative stress,[19] and enhanced
sympathetic output.[20] Even as the understanding of how OSA might lead to IR and
overt type 2 diabetes mellitus (DM) are far from complete, OSA should be considered
as an independent risk factor for the development of type 2 DM, and when coexisting
with COPD, the risks are likely to be higher. In this regard, a recent meta-analysis
performed by Yang et al. supported the beneficial effects of CPAP on the glucose metabolism.[21]
COPD is also associated with an increased risk of hyperglycemia. In the Nurses’ Health
Study that was conducted prospectively over an 8-year period, COPD patients had a
1.8 times risk of developing diabetes. Markers of inflammation such as IL-6, TNF-α,
and C-reactive protein (CRP) are elevated in both COPD and diabetes, and these markers
are elevated to a greater extent in overweight and obese COPD patients.[22] Mannino
et al. showed that cases with stage 3-4 COPD had a higher risk for developing diabetes
with an odds ratio of 1.5.[23] MetS may also increase the risk of a COPD exacerbation
with associated hyperglycemia, hypertriglyceridemia, and CRP elevation.[21] Hypoxia
may also modulate IR and detrimental effects on glucose metabolism in COPD cases through
alterations in the hypoxia-inducible factor family. MetS also represents a risk factor
for the development of all forms of pulmonary vascular disease and right ventricular
(RV) dysfunction.[24] Patients with pulmonary arterial hypertension exhibit an increased
prevalence of glucose intolerance and IR, which is associated with changes in RV structure
and function. The potential mechanisms by which MetS causes RV dysfunction include
mitochondrial dysfunction with a shift in cardiomyocyte energy utilization from fatty
acid oxidation to glucose which reduces the mitochondrial use of lipids, leading to
cytoplasmic accumulation and deposition of lipid intermediaries, a condition known
as “lipotoxic cardiomyopathy.”[24
25]
The pathogenesis of lung disease and MetS is multifactorial. The two share a number
of risk factors including smoking, genetics, obesity, physical inactivity, and airflow
limitation.[26] COPD has been proposed to be chronic inflammatory disorder,[27] with
a surge in circulatory inflammatory markers irrespective of the severity of the impairment
of lung function.[28] Circulatory inflammatory markers such as TNF-α, CRP, lipopolysaccharide-binding
protein, lipid peroxidation products, inflammatory cells, markers of with neutrophilic
inflammation (matrix metalloproteinase-9 [MMP-9], elastase, calprotectin, MMP-9/tissue
inhibitor of metalloproteinase-1 ratio, IL-6, BAL neutrophils), and proinflammatory
markers (IL-6, IL-β, IFN-α, I, monokine induced by gamma interferon, and macrophage
inflammatory protein 1 alpha) are found to be significantly elevated in patients with
COPD.[29
30] Inflammatory biomarkers in respiratory specimens such as sputum, BAL, and endobronchial
biopsy have also been found to demonstrate a heightened expression in COPD[31] and
are considered to be part of a “spill over” of the inflammatory mediators from the
pulmonary compartment which is primarily responsible for systemic inflammation. Systemic
inflammation may probably be the common pathogenic mechanism responsible for genesis
of COPD and its other comorbidities such as the MetS.[32
33] However, recent data from the ECLIPSE study showed a poor correlation between
sputum neutrophils and severity of COPD; thus, there was no significant association
with the severity of inflammation and the exacerbation rate of COPD.[34] Even intervention
studies in COPD-like monoclonal antibodies against IL-8 and anti-TNF-α antibodies
– infliximab – do not significantly modify the local or systemic inflammatory mediators.
These observations further shroud our understanding of the underlying pathogenetic
mechanisms responsible for the development of MetS in COPD.
In summary, abundant epidemiological and clinical evidence exists to support the important
link between MetS and lung function impairment; however, the exact nature of this
relationship remains unknown even though the proposed mechanistic pathways strongly
suggest the association to be causal. Given the wide prevalence of MetS in the general
population, it is imperative that we continue to further understand how the two impact
each other so as to draft appropriate management strategies.