·Letter
to the Editor·
Ocular hypertension secondary to obesity: cortisol, the
missing piece of the pathophysiological puzzle?
Andrej Belančić1, Marija Krpina1, Sanja Klobučar Majanović1,2, Maja Merlak1,3
1University of Rijeka, Faculty of Medicine, Rijeka
51000, Croatia
2Department of Endocrinology, Diabetes and Metabolic
Diseases, Clinical Hospital Centre Rijeka, Rijeka 51000, Croatia
3Department of Ophthalmology, Clinical Hospital Centre
Rijeka, Rijeka 51000, Croatia
Correspondence to: Andrej
Belančić. University of Rijeka, Faculty of Medicine, Braće Branchetta 20,
Rijeka 51000, Croatia. a.belancic93@gmail.com
Received:
DOI:10.18240/ijo.2019.06.28
Citation:
Belančić A, Krpina M,
Klobučar Majanović S, Merlak M. Ocular
hypertension secondary to obesity: cortisol, the missing piece of the
pathophysiological puzzle? Int J
Ophthalmol
2019;12(6):1050-1051
Dear Editor,
Obesity has nowadays become a global public health challenge due to its
rapidly growing prevalence and interconnection with a wide spectrum of
comorbidities. A positive association of obesity with intraocular pressure
(IOP) and glaucoma status has been confirmed in majority of studies[1]. Several etiology theories have been proposed: 1)
excess in intraorbital adipose tissue, an increase in episcleral venous
pressure and consequent impairment of aqueous outflow facility; 2) increased
blood viscosity (red cell count, hemoglobin, hematocrit) and consequent
increase in outflow resistance of episcleral veins; 3) increased ciliary artery
pressure and aqueous humor ultrafiltration secondary to elevated blood
pressure; 4) osmotic fluid shift into the intraocular space due to
hyperglycemia. However, clear pathophysiological explanation for the
association between obesity and ocular hypertension is currently lacking[1]. Hence, that provoked us to try to solve the
pathophysiological puzzle.
Steroid-induced ocular hypertension was first described by McLean in 1950,
who documented IOP elevation after systemic administration of
adrenocorticotrophic hormone (ACTH). Side-effect of local corticosteroid
administration was reported four years later by Francois. Nowadays it is well
known that ocular hypertension can occur as a side-effect of both intravenous,
topical, oral, inhaled, periocular and intravitreal corticosteroid therapy[2]. Furthermore, cases of increased IOP and open-angle
glaucoma secondary to endogenous hypercortisolism (Cushing’s syndrome/disease)
are also well-documented[3]. It has also been
reported that IOP in normal healthy subjects fluctuates diurnally with its peak
at around
Results of our preliminary cross-sectional study, conducted on 50 obese
adults (80.0% female, median age of 44 years, body mass index 42.0±
To clarify, abdominal/visceral obesity phenotype is associated with chronic
hypothalamic-pituitary-adrenal axis hyperactivity, which leads to a condition
of functional hypercortisolism[4].
11β-hydroxysteroid dehydrogenase (11β-HSD) type 1 is overexpressed in adipose
tissue of obese individuals and what is more, it positively correlates with
measures of total (body mass index, body fat percentage) and central (waist
circumference) adiposity, fasting glucose, insulin and insulin resistance[5]. 11β-HSD1 is a microsomal enzyme, expressed mainly in
adipose tissue and liver, acting primarily as a nicotinamide adenine
dinucleotide phosphate-dependent reductase in vivo interconverting
inactive cortisone to active cortisol, thereby amplifying glucocorticoid
receptor activation. The contrasting isoform, 11β-HSD2 is predominantly
expressed in mineralocorticoid target tissues, where it inactivates cortisol to
cortisone thus excluding cortisol from exerting effects on non-selective
mineralocorticoid receptors[6]. At this point it
is of high importance to highlight that the presence of glucocorticoid and
mineralocorticoid receptors and 11β-HSD in human and mammalian ocular tissues
has been demonstrated in several studies[7].
Cortisol/cortisone ratio in the aqueous humour of 14:1 is suggested for
predominant 11β-HSD1 activity[7]. Consequently, it
is plausible that cortisol generation by overexpressed 11β-HSD1 (cortisone
reductase) stimulates serum and glucocorticoid-regulated kinase isoform 1 to
increase epithelium Na+ transport and aqueous humor production[8]. On top of that, there is also a simultaneous decrease
in aqueous humor outflow facility, since glucocorticoids are connected with
miscellaneous effects on trabecular meshwork cells causing changes in
trabecular meshwork protein expression, cytoskeletal organization,
extracellular matrix deposition, cell shape and cell function, etc[2,9]. Finally, inhibition of 11β-HSD
Last but not least, it is very interesting to highlight that cortisol is
even a common link/denominator between the previously published (inidicated
above as 1-4) obesity-related ocular hypertension theories. Cortisol, through
its erythropoietic effects, may slightly increase blood viscosity[10]. Second, cortisol increases arterial blood pressure
through interplay between several pathophysiological mechanisms: intrinsic
mineralocorticoid activity; activation of the renin-angiotensin system;
enhancement of cardiovascular reactivity to vasoconstrictors (catecholamines,
vasopressin, angiotensin II); increased β-adrenergic receptor sensitivity to
catecholamines; supression of the vasodilatory systems (NO synthase,
prostacyclin, kinin-kallikrein); increased cardiac output, total peripheral
resistance and renovascular resistance[11].
Furthermore, increased blood pressure is accompanied by increased ciliary
artery pressure and aqueous humor ultrafiltration. Third, glucocorticoids
enhance muscle protein breakdown, adipose tissue lipolysis, and hepatic tissue
gluconeogenesis, and reduce glucose utilization, effects that elevate
circulating glucose concentrations (whole-body insulin resistance), which may
result in osmotic fluid shift into the intraocular space[12].
To deduce, we hypothesize that cortisol is the missing link between obesity
and ocular hypertension and we propose the “cortisol” etiology theory.
ACKNOWLEDGEMENTS
Conflicts of Interest: Belančić A,
None; Krpina M, None; Klobučar Majanović S, None; Merlak M, None.
REFERENCES