Association of Dyslipidemia in Moderate to Severe Meibomian Gland Dysfunction

doi:10.1016/j.ajo.2010.04.016

American Journal of Ophthalmology

Volume 150, Issue 3, September 2010, Pages 371-375.e1

https://doi.org/10.1016/j.ajo.2010.04.016 Get rights and content

Purpose

To determine whether meibomian gland disease, a major contributor to dry eye syndrome, is associated with dyslipidemia.

Design

Retrospective case-control study.

Methods

setting: Clinical practice. patient or study population: Sixty-six patients from January 2008 to July 2009 with moderate to severe meibomian gland disease whose serum lipid levels were obtained. We excluded patients who were already taking lipid-altering substances and patients with rheumatologic disease. We analyzed several parameters in prevalence of dyslipidemia (total cholesterol > 200 mg/dL, low-density lipoprotein [LDL] > 130 mg/dL, high-density lipoprotein [HDL] < 40 mg/dL, and triglycerides >150 mg/dL) in MGD patients and compared these patients to the general population as reported by data from the National Health and Nutrition Examination Survey (NHANES). main outcome measure: The prevalence of dyslipidemia (elevated total cholesterol, elevated LDL, decreased HDL, or elevated triglycerides) in patients with moderate to severe MGD.

Results

Patients with moderate to severe MGD had a higher incidence of dyslipidemia with respect to elevated total cholesterol (>200 mg/dL), 67.4% to 45.1% (P = .0012) when compared to population controls. There was a smaller number of MGD patients with low HDL (HDL < 40 mg/dL), 6.5%, when compared to controls, 15.7% (P = .045). The incidence of increased LDL was not statistically significant (P = .184). There was a statistically smaller number of MGD patients with high triglycerides (TG > 150 mg/dL), 15.2%, when compared to controls, 33.1% (P = .0049).

Conclusions

Patients with moderate to severe MGD have a higher incidence of dyslipidemia with respect to elevated total cholesterol than the general population. Surprisingly, the component of total cholesterol that contributed most to this increase in total cholesterol came from elevated serum HDL levels. To our knowledge, elevated HDL has not been associated with any pathologic state. Patients with MGD had a statistically significant lower incidence of hypoalphalipoproteinemia (low HDL) than the general population. Patients with MGD also had a lower incidence of hypertriglyceridemia than the general population.

Section snippets

Materials and Methods

We reviewed the charts of patients in our clinic who were diagnosed with MGD since January 1, 2008. Treatment of our patients with MGD often includes the supplementation of 2000 to 4000 mg of an omega-3 fatty acid daily. Omega-3 fatty acid supplementation is known to alter lipid levels; therefore, we routinely order a baseline lipid panel, which includes HDL concentration, LDL concentration, triglycerides, and total cholesterol.

Patients were diagnosed with MGD by clinical examination based on

Results

Baseline lipid levels were recorded for 63 patients with MGD. Of these, 2 patients were excluded because of rheumatologic disease and 15 patients were excluded from the analysis because of their taking either an omega-3 fatty acid supplement (n = 6) or a statin (n = 9). Of the 46 remaining patients, 22 were male and 24 were female, the average age was 52.0 years, and the range in age was 27 to 82. We stratified our patients into age brackets (age 20–44, n = 17 [male n = 8, female n = 9]; age

Discussion

Patients with moderate to severe MGD have increased levels of total cholesterol compared to population controls. Increased cholesterol at the glandular secretion level has been studied and hypothesized to be a factor in meibomian gland dysfunction.3, 12

Because normal whole meibomian lipids have a melting point of 30°C to 34°C¹⁰ and cholesterol has a melting point of 148°C,¹⁰ increased concentration of cholesterol in meibomian lipid would increase the melting point of the meibomian lipid milieu,

Adam H. Dao, MD, graduated from the University of Texas Medical School at Houston in May 2010. He will be starting an Ophthalmology Residency at the University of South Carolina in 2011.

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Models for Meibomian gland dysfunction: In vivo and in vitro
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Meibomian gland dysfunction (MGD) is a chronic abnormality of the Meibomian glands (MGs) that is recognized as the leading cause of evaporative dry eye worldwide. Despite its prevalence, however, the pathophysiology of MGD remains elusive, and effective disease management continues to be a challenge. In the past 50 years, different models have been developed to illustrate the pathophysiological nature of MGD and the underlying disease mechanisms. An understanding of these models is crucial if researchers are to select an appropriate model to address specific questions related to MGD and to develop new treatments. Here, we summarize the various models of MGD, discuss their applications and limitations, and provide perspectives for future studies in the field.
The Yin and Yang of non-immune and immune responses in meibomian gland dysfunction
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Meibomian gland dysfunction (MGD) is a leading cause of dry eye disease and one of the most common ophthalmic conditions encountered in eye clinics worldwide. These holocrine glands are situated in the eyelid, where they produce specialized lipids, or meibum, needed to lubricate the eye surface and slow tear film evaporation – functions which are critical to preserving high-resolution vision. MGD results in tear instability, rapid tear evaporation, changes in local microflora, and dry eye disease, amongst other pathological entities. While studies identifying the mechanisms of MGD have generally focused on gland obstruction, we now know that age is a major risk factor for MGD that is associated with abnormal cell differentiation and renewal. It is also now appreciated that immune-inflammatory disorders, such as certain autoimmune diseases and atopy, may trigger MGD, as demonstrated through a T cell-driven neutrophil response. Here, we independently discuss the underlying roles of gland and immune related factors in MGD, as well as the integration of these two distinct mechanisms into a unified perspective that may aid future studies. From this unique standpoint, we propose a revised model in which glandular dysfunction and immunopathogenic pathways are not primary versus secondary contributors in MGD, but are fluid, interactive, and dynamic, which we likened to the Yin and Yang of MGD.
Integrated multi-omics and machine learning approach reveals lipid metabolic biomarkers and signaling in age-related meibomian gland dysfunction
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Meibomian gland dysfunction (MGD) is a prevalent inflammatory disorder of the ocular surface that significantly impacts patients’ vision and quality of life. The underlying mechanism of aging and MGD remains largely uncharacterized. The aim of this work is to investigate lipid metabolic alterations in age-related MGD (ARMGD) through integrated proteomics, lipidomics and machine learning (ML) approach. For this purpose, we collected samples of female mouse meibomian glands (MGs) dissected from eyelids at age two months (n = 9) and two years (n = 9) for proteomic and lipidomic profilings using the liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. To further identify ARMGD-related lipid biomarkers, ML model was established using the least absolute shrinkage and selection operator (LASSO) algorithm. For proteomic profiling, 375 differentially expressed proteins were detected. Functional analyses indicated the leading role of cholesterol biosynthesis in the aging process of MGs. Several proteins were proposed as potential biomarkers, including lanosterol synthase (Lss), 24-dehydrocholesterol reductase (Dhcr24), and farnesyl diphosphate farnesyl transferase 1 (Fdft1). Concomitantly, lipidomic analysis unveiled 47 lipid species that were differentially expressed and clustered into four classes. The most notable age-related alterations involved a decline in cholesteryl esters (ChE) levels and an increase in triradylglycerols (TG) levels, accompanied by significant differences in their lipid unsaturation patterns. Through ML construction, it was confirmed that ChE(26:0), ChE(26:1), and ChE(30:1) represent the most promising diagnostic molecules. The present study identified essential proteins, lipids, and signaling pathways in age-related MGD (ARMGD), providing a reference landscape to facilitate novel strategies for the disease transformation.
Alteration in meibum lipid composition and subjective symptoms due to aging and meibomian gland dysfunction
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To investigate the alteration in lipid composition of meibum, objective clinical signs, and subjective symptoms associated with aging and meibomian gland (MG) dysfunction (MGD).
In 10 MGD patients [4 males/6 females, mean age: 65.6 ± 7.9 years (range: 50–79 years)] and 24 healthy volunteer subjects [young subjects: 6 males/6 females, mean age: 25.7 ± 3.8 years (range: 20–35 years), elderly subjects: 6 males/6 females, mean age: 58.4 ± 7.5 years (range: 50–79 years)], three objective clinical signs were evaluated: MG orifice obstruction, meibum score, and tear film lipid layer interference pattern. Subjective symptoms were analyzed via a 15-item questionnaire. After careful collection of meibum samples, comprehensive lipid analysis was performed via liquid chromatography-mass spectrometry. Data was analyzed via JMP® ver. 13 (SAS Institute, Inc., Cary, NC) statistical analysis software.
In the MGD patients and elderly subjects, there was a significant decrease in non-polar lipids such as cholesterol esters (ChEs), while a significant increase in polar lipids [cholesterol (Ch), (O-acyl)-ω-hydroxy fatty acid (OAHFA), and free fatty acid (FA)] in total lipids (Tukey-Kramer test: p < 0.05). Triglyceride was significantly increased only in MGD patients (p < 0.05). Symptom scores representative of vision quality (i.e., blurred vision/haziness) were significantly negatively-correlated with the ratio of the non-polar lipid ChE, while significantly positively correlated with the polar lipids Ch, OAHFA, and FA (Spearman's rank correlation coefficient: p < 0.05).
Our findings revealed that both MGD and aging affect the composition ratio of major meibum lipids, resulting in the appearance of subjective symptoms.
Systemic Conditions Associated with Severity of Dry Eye Signs and Symptoms in the Dry Eye Assessment and Management Study
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Citation Excerpt :
Dyslipidemias, hypertension, and atherosclerotic diseases also have been associated disputably with DED prevalence.12,16,17,19,20,32–35,61 Increased cholesterol content in meibomian lipids may cause plugging of meibomian glands, with elevated high-density lipoprotein reported to be associated with moderate-to-severe MGD in a retrospective case-control study.33 In our study, 9% of patients (47 individuals) reported ongoing peripheral artery disease, 32% of patients (171 individuals) reported ongoing hypercholesterolemia, 28% of patients (149 individuals) reported ongoing hypertension, and 5% of patients (25 individuals) reported ongoing hypertriglyceridemia.
Certain systemic conditions are reported to be risk factors for dry eye disease (DED), but their associations with DED severity are not well studied. We evaluated whether systemic conditions reported to be DED risk factors are associated with severity of DED signs and symptoms.
Secondary analysis of data from the Dry Eye Assessment and Management Study, a large-scale multicenter randomized clinical trial of patients with moderate to severe DED.
Five hundred thirty-five adult patients with moderate to severe DED from 27 United States centers.
Patients reported their medical history at baseline. They underwent ocular surface examinations and symptom evaluation using standardized protocols at baseline, 6 months, and 12 months. We analyzed the associations of systemic conditions (a systemic disease or smoking history) reported as potential DED risk factors with the severity of DED signs and symptoms using generalized linear regression models adjusted by age, gender, race, and visit.
Dry eye disease symptoms assessed using the Ocular Surface Disease Index (OSDI), 6 DED signs (tear film break-up time, anesthetized Schirmer testing, corneal fluorescein staining, conjunctival lissamine green staining, tear osmolarity, and meibomian gland dysfunction), and a composite signs severity score from 0 to 1 (1 = most severe).
The mean age was 58 years; 81% were women. More severe DED signs were associated significantly with Sjögren syndrome (mean composite signs severity score 0.52 with disease vs. 0.43 without disease; P < 0.001), facial rosacea (0.47 vs. 0.43; P = 0.002), rheumatoid arthritis (0.47 vs. 0.42; P = 0.002), peripheral artery disease (0.50 vs. 0.43; P < 0.001), and daily smoking history (0.45 vs. 0.43; P = 0.047). Thyroid dysfunction, osteoarthritis, diabetes, irritable bowel syndrome, hypercholesterolemia, hypertension, and hypertriglyceridemia were not associated significantly with DED signs. No conditions were associated significantly with OSDI.
In this large, well-characterized cohort of patients with DED assessed under standardized procedures, patients with certain systemic diseases and smoking history showed more severe DED signs compared with patients without the conditions. The profile of significant DED signs varied by systemic condition, reflecting different DED causes. Understanding the systemic conditions and underlying causes that predispose some patients to severe DED can improve management.
Differential effects of dietary cholesterol and triglycerides on the lipid homeostasis in Meibomian glands
2021, Journal of Steroid Biochemistry and Molecular Biology
Exocrine Meibomian glands (MG) play a central role in the ocular surface physiology by producing meibum – a lipid secretion composed of cholesteryl esters (CE), cholesterol (Chl), triacylgycerols (TAG), waxes and other types of lipids. MG were previously shown to synthesize Meibomian lipids (ML) in situ via a complex array of reactions termed meibogenesis. However, questions remain about the role of dietary lipids in meibogenesis. To establish if dietary Chl (DC) and TAG (DT) can participate in meibogenesis, we studied mice whose diet was supplemented with trace amounts of deuterated Chl (²H-Chl) and ¹³C-labeled triolein (¹³C-TO), and the products of their biosynthetic transformations were analyzed using LC/MS. We demonstrated that ²H-Chl, but not ¹³C-TO, could be directly incorporated into meibum. Furthermore, ²H-Chl was esterified into MG-specific ultra long ²H-CE, which were vastly different from plasma CE and ²H-CE. The measured ²H-Chl/Chl and ²H-CE/CE ratios in meibum increased in a time-dependent manner reaching ∼5% and ∼1.2 %, respectively. The ²H-Chl/²H-CE ratio was about 3.5x higher than that for endogenous unlabeled Chl and CE, indicating accumulation of ²H-Chl in meibum. The elongation pattern of Meibomian ²H-CE closely replicated that of unlabeled CE. On the other hand, ¹³C-TO was not detected in any of the ML samples as an intact lipid or its metabolized/hydrolyzed products. We conclude that DC can be directly esterified into MG-specific CE, while DT undergo extensive catabolic transformations before reaching MG. These findings demonstrate that DC can have a direct impact on MG and ocular surface lipid homeostasis and pathophysiology.

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Adam H. Dao, MD, graduated from the University of Texas Medical School at Houston in May 2010. He will be starting an Ophthalmology Residency at the University of South Carolina in 2011.

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Original articleAssociation of Dyslipidemia in Moderate to Severe Meibomian Gland Dysfunction

Purpose

Design

Methods

Results

Conclusions

Section snippets

Materials and Methods

Results

Discussion

Surv Ophthalmol

Surv Ophthalmol

Ocul Surf

Prog Retin Eye Res

Exp Eye Res

Meibomian gland disease: classification and grading of lid changes

Eye

Criteria for the evaluation of lid margin in blepharitis

Invest Ophthalmol Vis Sci

Original article
Association of Dyslipidemia in Moderate to Severe Meibomian Gland Dysfunction