Re: Short term use of oral corticosteroids and related harms among adults in the United States: population based cohort study
The observation that the intake of corticosteroids even for short durations at small doses leads to an increase in the rate of infections, thromboembolism and fractures (1) is of clinical importance. It is relevant that a single injection of 100 mg of hydrocortisone inhibits reactive oxygen species (ROS) generation by peripheral blood mononuclear cells (MNC) and polymorphonuclear (PMN) leukocytes by over 40% and that of 300 mg (=60 mg prednisolone) by 95% (2, 3). Since ROS mediate bacterial killing by these cells, such an inhibition while being useful for the mediation of an anti-inflammatory effect, is likely to make a patient vulnerable to infections. The inhibition of ROS generation is associated with the suppression of the expression of p47phox an essential subunit of the enzyme NADPH oxidase which generates the superoxide radical (4). Hydrocortisone injection also suppresses intranuclear NFkB binding and increase in IkBα expression. In addition, 100 mg of hydrocortisone or 4 mg of dexamethasone also induce the release of IL-10 (5), an anti-inflammatory cytokine which may suppress the inflammatory response to an infection, thus allowing the infection to linger. Furthermore, the injection of 300 mg of hydrocortisone results in the induction of pro-inflammatory mediators like HMG-B1 which modulate the transcription of pro-inflammatory genes while in their native intranuclear setting and which activate inflammation through AGE receptors (RAGE) when in plasma (6). In addition, 300 mg of hydrocortisone induces an increase in the expression of TLR-2, TLR-5 and TLR-9 in MNC. Plasma concentration of MMP-9 increases with 300 mg of hydrocortisone (6) while the smaller 100 mg dose of hydrocortisone suppresses MMP-9.
As far as the increase in fracture rate is concerned, our work shows the even a single dose of 300 mg of hydrocortisone results in the suppression of osteocalcin, a product of the osteoblast and osteoprotegerin, which binds to RANK-L and thus prevents its activation of the osteoclast. Thus, even a single high dose of hydrocortisone inhibits osteoblastic activity and potentially enhances osteoclastic activity (unpublished observations). Our observations on the acute effects of a single dose of hydrocortisone are qualitatively similar to those of prolonged corticosteroid treatment.
It is, therefore, not surprising that even a small duration of corticosteroid treatment results in increased rates of infections and fractures.
References:
1. Waljee AK, Rogers MA, Lin P, Singal AG, Stein JD, Marks RM, Ayanian JZ, and Nallamothu BK. Short term use of oral corticosteroids and related harms among adults in the United States: population based cohort study. BMJ. 2017;357(j1415.
2. Dandona P, Suri M, Hamouda W, Aljada A, Kumbkarni Y, and Thusu K. Hydrocortisone-induced inhibition of reactive oxygen species by polymorphonuclear neutrophils. Crit Care Med. 1999;27(11):2442-4.
3. Dandona P, Thusu K, Hafeez R, Abdel-Rahman E, and Chaudhuri A. Effect of hydrocortisone on oxygen free radical generation by mononuclear cells. Metabolism. 1998;47(7):788-91.
4. Dandona P, Aljada A, Ghanim H, Mohanty P, Hamouda W, and Al-Haddad W. Acute suppressive effect of hydrocortisone on p47 subunit of nicotinamide adenine dinucleotide phosphate oxidase. Metabolism. 2001;50(5):548-52.
5. Dandona P, Aljada A, Garg R, and Mohanty P. Increase in plasma interleukin-10 following hydrocortisone injection. J Clin Endocrinol Metab. 1999;84(3):1141-4.
6. Dandona P, Ghanim H, Sia CL, Green K, Abuaysheh S, Dhindsa S, Chaudhuri A, and Makdissi A. A mixed anti-inflammatory and pro-inflammatory response associated with a high dose of corticosteroids. Curr Mol Med. 2014;14(6):793-801.
Competing interests:
No competing interests
08 May 2017
Paresh Dandona
SUNY Distinguished Professor of Medicine
Husam Ghanim, PhD
State University of New York at Buffalo
1000 Youngs Road, Suite 105, Williamsville NY 14221
Rapid Response:
Re: Short term use of oral corticosteroids and related harms among adults in the United States: population based cohort study
The observation that the intake of corticosteroids even for short durations at small doses leads to an increase in the rate of infections, thromboembolism and fractures (1) is of clinical importance. It is relevant that a single injection of 100 mg of hydrocortisone inhibits reactive oxygen species (ROS) generation by peripheral blood mononuclear cells (MNC) and polymorphonuclear (PMN) leukocytes by over 40% and that of 300 mg (=60 mg prednisolone) by 95% (2, 3). Since ROS mediate bacterial killing by these cells, such an inhibition while being useful for the mediation of an anti-inflammatory effect, is likely to make a patient vulnerable to infections. The inhibition of ROS generation is associated with the suppression of the expression of p47phox an essential subunit of the enzyme NADPH oxidase which generates the superoxide radical (4). Hydrocortisone injection also suppresses intranuclear NFkB binding and increase in IkBα expression. In addition, 100 mg of hydrocortisone or 4 mg of dexamethasone also induce the release of IL-10 (5), an anti-inflammatory cytokine which may suppress the inflammatory response to an infection, thus allowing the infection to linger. Furthermore, the injection of 300 mg of hydrocortisone results in the induction of pro-inflammatory mediators like HMG-B1 which modulate the transcription of pro-inflammatory genes while in their native intranuclear setting and which activate inflammation through AGE receptors (RAGE) when in plasma (6). In addition, 300 mg of hydrocortisone induces an increase in the expression of TLR-2, TLR-5 and TLR-9 in MNC. Plasma concentration of MMP-9 increases with 300 mg of hydrocortisone (6) while the smaller 100 mg dose of hydrocortisone suppresses MMP-9.
As far as the increase in fracture rate is concerned, our work shows the even a single dose of 300 mg of hydrocortisone results in the suppression of osteocalcin, a product of the osteoblast and osteoprotegerin, which binds to RANK-L and thus prevents its activation of the osteoclast. Thus, even a single high dose of hydrocortisone inhibits osteoblastic activity and potentially enhances osteoclastic activity (unpublished observations). Our observations on the acute effects of a single dose of hydrocortisone are qualitatively similar to those of prolonged corticosteroid treatment.
It is, therefore, not surprising that even a small duration of corticosteroid treatment results in increased rates of infections and fractures.
References:
1. Waljee AK, Rogers MA, Lin P, Singal AG, Stein JD, Marks RM, Ayanian JZ, and Nallamothu BK. Short term use of oral corticosteroids and related harms among adults in the United States: population based cohort study. BMJ. 2017;357(j1415.
2. Dandona P, Suri M, Hamouda W, Aljada A, Kumbkarni Y, and Thusu K. Hydrocortisone-induced inhibition of reactive oxygen species by polymorphonuclear neutrophils. Crit Care Med. 1999;27(11):2442-4.
3. Dandona P, Thusu K, Hafeez R, Abdel-Rahman E, and Chaudhuri A. Effect of hydrocortisone on oxygen free radical generation by mononuclear cells. Metabolism. 1998;47(7):788-91.
4. Dandona P, Aljada A, Ghanim H, Mohanty P, Hamouda W, and Al-Haddad W. Acute suppressive effect of hydrocortisone on p47 subunit of nicotinamide adenine dinucleotide phosphate oxidase. Metabolism. 2001;50(5):548-52.
5. Dandona P, Aljada A, Garg R, and Mohanty P. Increase in plasma interleukin-10 following hydrocortisone injection. J Clin Endocrinol Metab. 1999;84(3):1141-4.
6. Dandona P, Ghanim H, Sia CL, Green K, Abuaysheh S, Dhindsa S, Chaudhuri A, and Makdissi A. A mixed anti-inflammatory and pro-inflammatory response associated with a high dose of corticosteroids. Curr Mol Med. 2014;14(6):793-801.
Competing interests: No competing interests