The Yin and Yang of Steroids

In Chinese philosophy, yin represents the negative and yang represents the positive, and their interaction influences the destiny of individuals. So it is with steroids, the most widely used drugs in the world for the treatment of immune and inflammatory diseases. Unfortunately, steroids are non-specific in their action and hence arouse concerns about their side effects.

Inflammation is the underlying pathogenesis of asthma. Allergens and/or irritants trigger the infiltration and activation of a variety of inflammatory cells and subsequent mediators that result in inflammation in the airways. To date, the most important anti-inflammatory pharmacologic treatment of asthma requires the use of steroids. “Steroids” refer to glucocorticosteroids or glucocorticoids and are the mainstay of treatment in asthma. Being glucocorticosteroids, they should not be confused with illegal anabolic steroids. Glucocorticosteroids are similar to the natural hormone cortisone produced by the adrenal gland, while anabolic steroids are similar to the natural male sex hormones and are used to build muscle with disastrous effects on the body.

In asthma, steroids are used to suppress the inflammatory response and are prescribed in basically two forms –  inhaled corticosteroids (ICS) which are the basis for treating asthma on a daily basis; and oral form (OCS) which is generally used to handle moderate to severe exacerbations.

In terms of duration, steroids may be grouped as:

  • short-acting – cortisol, hydrocortisone (water-soluble)
  • intermediate acting – prednisone, prednisolone, triamcinolone and methylprednisone
  • long-acting – dexamethasone andbetamethasone

In general, steroids1,2

  • improve airway inflammation
  • suppress the inflammatory genes excited in asthma
  • inhibit the many inflammatory pathways
  • reduce inflammatory cell infiltrate
  • increase the number of neutrophils
  • inhibit goblet cell hyperplasis
  • decrease vascularity
  • inhibit permeability linked to inflammation

The ICS are measured in micrograms (one millionth of a milligram). Since they are inhaled, they go directly into the lungs. They are effective in increasing FEV1, reducing bronchial responsiveness, exhaled NO and sputum eosinophilia.

Low doses of ICS only reduce the infiltration of inflammatory cells into airway cells. At high doses ICS may reduce the number of inflammatory cells in the airways and affect elements of airway remodeling such as the thickness of the basement membrane and the vascularity of the airway walls.3

ICS do have side effects such as hoarseness and thrush, which can be mitigated by using the ‘rinse and spit’ tactic after inhalation. However, high doses of ICS can have systemic effects, as shown in Table 1. Inhaled corticosteroids also affects bone mineral density, with an increased risk of fractures as the dose increases. The risk is significant at high doses.4 A dose-response link is also seen between diabetes incidence and use of ICS.5

Children on ICS may see a loss of height, particularly in the first year.6 This failure to grow normally is dependent on the duration of treatment and adrenal suppression is likely if the dosage exceeds the recommended range. Some children will have systemic side effects to ICS, particularly in those with severe, difficult-to-control asthma. Some children may also over time become steroid resistant and these should be seen by a specialist.

ICS can also cause myopathy. Levin et al7 evaluated skeletal muscle function in 36 individuals with respiratory disease who were taking ICS daily for a year or more. They concluded that a year of daily intake of ICS causes significant loss of muscle function, for they found

  • 65% reported muscle weakness in legs
  • 20% showed objective signs of weakness

Some patients respond poorly or not at all to ICS treatment. Persons with asthma who smoke tobacco or who are exposed to secondhand smoke also exhibit a reduced response to ICS and tend to have more severe asthma.1

Systemic side effects are associated with the fluorinated steroids, which include beclomethasone, betamethasone, desamethasone and triamcinolone.  

Briefly stated, being powerful hormones, oral steroids have major side effects that include:8-10

  • adrenal suppression
  • impaired bone metabolism (osteomalacia or softening of the bone and osteoporosis)
  • linear growth delay in children
  • cataracts
  • diabetes
  • infection
  • myopathy (muscle weakness, wasting and changes within muscle cells)
  • hypertension (rise in blood pressure)
  • impaired immune response that may lead to increased risk of unusual infections
  • aseptic necrosis of the hip (death of bone tissue)
  • impairment of wound healing
  • suppression of the patient’s own steroid production and hence an effect on the stress response
  • psychiatric disturbance

Minetto and colleagues11 wanted to measure the short-term effects of steroids on healthy men, and so five such men were given dexamethasone for 7 days. They were able to detect and measure the loss of both cross-sectional area and specific force in muscle fibres that likely predicted the beginning of myopathy due to steroids. They concluded that iIndividuals who take oral steroids, particularly fluorinated steroids, are at greater risk for steroid-induced myopathy. However, discontinuance of ICS or OCS does tend to revert the process though partial or complete recovery can take a long time.

Less important side effects include:

  • bruising
  • thinning of the skin
  • increased appetite
  • weight gain
  • mood change
  • acne
  • “moon face”
  • hirsutism (excessive hair growth)
  • insomnia
  • nightmares
  • fat accumulation and stretch marks

Mood changes – from depression to euphoria to aggression – are common with patients on steroids and are also seen on patients coming off steroids. Cessation of steroid therapy must be done under professional supervision particularly for steroid-dependent patients with severe asthma. Patients are usually given a short burst that lasts less than a week, but they should be made aware that they can have some of these side effects, particularly depression. Multiple short bursts can also result in osteopenia (thinning of the bone), particularly in pre-pubertal boys.12

While steroids are literally life-saving for patients having a severe or acute asthma exacerbation, they are nonetheless powerful medications with serious side effects, and should be administered with appropriate care. It is particularly incumbent on the health professional to consider the total amount being administered since steroids are used in the treatment of many diseases – renal, neurologic, rheumatologic, for malignancy, for immunosuppression, etc. They are also used in skin disorders and in occlusive dressings. Hence, where possible, the total amount of exposure should be calculated and every effort made to minimize the dose and duration of steroid treatment. Careful monitoring of patients, particularly of growth in children, is essential for the steroids to be a blessing and not a curse.

References

  1. Barnes PJ. How corticosteroids control inflammation. Quintiles Prize Lecture 2005. Br J Pharmacol. 2006 Jun;148(3):245-54.  doi:  10.1038/sj.bjp.0706736
  2. Hamid Q. Effects of steroids on inflammation and cytokine gene expression in airway inflammation. JACI 2003;112(3):636-8.
  3. Chetta, Marangio E, Olivieri D. Inhaled steroids and airway remodelling in asthma. Acta Biomed. 2003; 74(3):121-5
  4. Kelly HW, Nelson HS. Potential adverse effects of the inhaled corticosteroids. J Allergy Clin Immunol. 2003;112(3):469-78;
  5. Ernst P, Suissa S. Systemic effects of inhaled corticosteroids. Curr Opin Pulm Med. 2012;18(1):85-9.
  6. Pruteanu A, Chauhan BF et al. Inhaled corticosteroids in children with persistent asthma: dose-response effects on growth. The Cochrane Library. DOI: 10.1002/14651858.CD009878.pub2
  7. Levin OS, Polunina AG et al. Steroid myopathy in patients with chronic respiratory diseases. J Neurol Sci. 2014; 338(1-2): 96-101. Abstract.
  8. Monson JP. Systemic effects of inhaled corticosteroids. Thorax 1993: 48:955-6
  9. Leblanc RA, Paquette L et al. Skin bruising in asthmatic subject treated with high doses of inhaled steroids: frequence and association with adrenal function. Eur Respir J 1996; (2): 226-314.
  10. Mrazek DA. Psychiatric complications of pediatric asthma. Ann Allergy 1992: 69:285-90
  11. Minettto MA, Qaisar R et al. Quantitative and qualitative adaptations of muscle fibres to glucocorticoids. Muscle Nerve. 2015. Doi:10.1002/mus.24572
  12. Kelly HW, Van Natta ML, Covar RA, et al. Effect of long-term corticosteroid use on bone mineral density in children: a prospective longitudinal assessment in the childhood Asthma Management Program (CAMP) study. Pediatrics. 2008 ;122 (1): 53-61.