Management of patients on systemic steroids: An oral surgery perspective

Physiology of corticosteroids

Steroidogenesis is a complex and sensitive process that occurs in the cortex of the adrenal gland. An imbalance in production of corticosteroids may have severe effects on multiple organs. The steroids produced can be divided into two groups: mineralocorticoids and glucocorticoids. Mineralocorticoids, such as aldosterone, are important in regulating the body's water, electrolyte balance and blood pressure.⁴ Angiotensin II and potassium concentration in the extracellular fluid are key in controlling aldosterone levels. They tend to be regulated by the renin–angiotensin system. Glucocorticoids, notably cortisol, play a pivotal role in stress management, the immune response, as well as glucose and protein homeostasis. Cortisol levels rise during stress via the release of the cytokine, interleukin-1, which results in mobilization of fat and glycogen stores. Cortisol and aldosterone are composed of similar base structures, and so overlap in many functions. One key function that both steroids play a pivotal role in is, the regulation blood pressure, and thus there is a strong relation between steroids and blood pressure.

Cortisol is synthesized by the cells of the zona fasiculata and zona reticularis of the adrenal cortex. The role of zone reticularis is to store cholesterol for steroidogenesis and secrete sex hormones. It is prudent to note that hormones produced in the cortex all share a degree of common function. The release of cortisol is controlled by the hypothalamic–pituitary–adrenal (HPA) axis. Corticotrophin-releasing hormone (CRH), which is released by the hypothamalamus, acts on the anterior pituitary gland to stimulate the release of adenocorticotropic hormone (ACTH), which in turn acts on the adrenal cortex. A negative feedback loop exists in that sufficient cortisol levels will inhibit further production of CRH and ACTH (Figure 1).⁵ However, in times of stress, particularly trauma and anxiety, this negative feedback mechanism may be bypassed and CRH increased in order to accommodate for the increased need for glucocorticoids.^6,7 The HPA axis follows a circadian rhythm, with cortisol levels high in the morning and low at night. Endogenous production of cortisol is believed to be 24–30 mg/day (equivalent to 5–7.5 mg prednisolone), and is expected to rise as high as 300 mg/day (equivalent to 60 mg prednisolone) when under stress.⁸ Efficacy of the adrenal gland in producing cortisol can be measured by a short synacthen test.⁹ This test measures blood cortisol level changes before and after the introduction of synacthen, a chemical copy of ACTH. Interestingly, emerging studies have described that patients with adrenal insufficiency are at an increased risk of acquiring COVID-19 and have a higher risk of complications owing to the potential of infection to trigger an adrenal crisis.¹⁰

Therapeutic uses of glucocorticoids

Corticosteroid drugs are synthetic analogues of cortisol hormone. They bind to specific intracellular glucocorticoid receptors upon entering target tissues and mimic the effects of the naturally occurring hormones. The onset of systemic glucocorticoids is often delayed (3–8 hours), and thus early provision of these drugs is crucial in treatment. As the surface receptors for steroids are located in the cytoplasm, they must travel to the nucleus to enable gene expression, this long journey can account for the effects persisting beyond the metabolism of the drug. Glucocorticoids are used either singly or in combination with other drugs in the treatment of a wide variety of medical disorders (Table 1).¹¹ Commonly used corticosteroids are listed in Table 2.¹⁵

Primary adrenal insufficiency

Primary adrenal insufficiency (PAI) can be defined by the inability of the adrenal cortex to produce sufficient amounts of glucocorticoids and/or mineralocorticoids.¹² PAI was first described by Thomas Addison in 1855, and it is hence commonly termed Addison's disease. The incidence is thought to be 6 people per million of the population per year. Presentation is most prevalent between the ages of 30 and 50 years and more commonly associated with women.¹³

Autoimmune destruction of the adrenal glands is currently thought to be the most common cause of Addison's disease (approximately 70% of all cases): these patients are more likely to have polyglandular autoimmune syndromes. Infections such as tuberculosis, sepsis, cytomegalovirus and HIV have also been associated with adrenal insufficiency. Other causes of PAI include haemorrhagic infarction caused by adrenal vein thrombosis, metastatic cancers, drugs that alter cortisol biosynthesis (aminoglutethemide, etomidate) or cortisol metabolism (phenytoin, barbiturates) and adrenalectomy.

Clinical presentation, which usually occurs when >90% of the adrenal cortices have been lost, includes fatigue, weakness, nausea and skin hyperpigmentation. As cortisol levels fall in primary adrenal insufficiency, the pro-hormone peptide, pro-opiomelanocortin (POMC) levels rise. POMC is responsible for producing ACTH, which in turn produces α-melanocyte-stimulating-hormone (αMSH) as a cleavage product. It is αMSH that is the most important hormone involved in melanogenesis and hyperpigmentation in this patient group.¹⁴ PAI is a chronic illness in which high-stress scenarios can precipitate acute episodes, commonly known as an Addisonian or adrenal crisis (AC). An increase in cortisol level is required to meet the body's increased physiological requirements during stress. Unfortunately for this patient group, endogenous cortisol production is restricted, and so to prevent an AC, additional steroid cover is often required. PAI patients are usually managed with life-long corticosteroid replacement therapy. Corticosteroid therapy usually consists of:

Dual release systems, such as Entyvio (Takeda, Japan) and Plenadren (Takeda, UK), are thought to better mimic normal circadian cortisol rhythm and are currently being trialed for use. Chronic exposure to high endogenous or exogenous cortisol levels may result in individuals to become Cushingoid. It is important to note that Cushing's syndrome is caused by an increase in steroids from the adrenal cortex, while Cushing's disease results from increased ACTH production from the pituitary gland. Patients with Cushing's syndrome usually exhibit the following clinical presentation: plethora (red face), moon face, acne, capillary fragility and bruising, diabetes (raised blood sugar), atherosclerosis, hypertension, osteoporosis and muscle weakness.¹⁶

Secondary and tertiary adrenal insufficiency

Secondary adrenal insufficiency may be caused by any disease that affects the anterior pituitary gland or interferes with ACTH secretion.¹⁷ Furthermore, chronic use of exogenous glucocorticoids can result in adrenal gland suppression and subsequent atrophy. In these cases, a decrease in glucocorticoid levels may be seen; however, mineralocorticoid levels are not usually suppressed because they are controlled by the renin–angiotensin system. Tertiary adrenal insufficiency aetiology is associated with impaired function of the hypothalamus or impaired secretion of CRH, which in turn causes a reduction in ACTH. Patients with secondary or tertiary adrenal insufficiency preserve mineralocorticoid function, which is important as this reduces the severity of symptoms when compared to primary adrenal deficiency (particularly dehydration and hyperkalaemia).¹⁸ This phenomenon is primarily evident as blood pressure remains stable, and therefore, postural hypotension is less common than in PAI. It is important to note that adrenal gland atrophy will inevitably result in decreased glucocorticoid response to stress, and so an adrenal crisis may also be precipitated in this patient group.

Adrenal/Addisonian crisis

Adrenal crisis (AC) is a serious complication in patients with severe glucocorticoid deficiency. This medical emergency is precipitated by the inability of the adrenal cortex to produce sufficient cortisol at times of significant stress. General anaesthesia, infection, stress and pain are factors known to increase the risk of AC in predisposed patients.¹⁹ It is estimated that there is an incidence rate of 5–10 adrenal crises/100 patient years and a mortality rate of 1/100 years.²⁰ AC in children is understood to be rare. The condition initially develops slowly over a few hours and is followed by severe systemic manifestation (Table 3).²¹ Early diagnosis of AC is crucial as patient deterioration is rapid and can result in hypothermia, hypoglycaemia, severe hypotension, circulatory collapse or death. It is important for the reader to remind themselves that postural hypotension within dentistry is not common owing to normal aldosterone levels in patients with secondary adrenal insufficiency; severe presentation of AC symptoms, such as postural hypotension, are not as common. Management of AC is described in Figures 2 and 3.³⁶

Evidence for provision of steroid cover

To date, there have been six cases of AC reported following dental procedures, usually associated with post-operative hypotension.^22,23 The Royal College of Physicians and the Society of Endocrinology guidance states that prednisolone doses of 5 mg/day can cause suppression of the HPA axis.²⁴ Depending on the cause and curative regimen, HPA axis recovery after steroid therapy is generally deemed to be 3 months. It is widely accepted that the degree of HPA suppression is related to the length of treatment and steroid therapy used (dose and duration).²⁵ Therefore, patients who have stopped taking steroids for 3 months or more, and those taking steroid doses equivalent to less than 5 mg prednisolone/day are low risk and do not usually require steroid cover.²⁶ In relation to this, the clinician should question the following.

Providing additional steroid cover

The concept of pre- and intra-operative steroid cover was first introduced in the mid-1950s to prevent an AC in steroid-supplemented patients. Consensus between medical and dental professions on a definitive protocol has long since been subject to debate.

When steroid cover is being considered, the clinician and patient should agree on the protocol, provided the risks and benefits are thoroughly discussed. If there is any doubt, it is advisable to contact the patient's endocrinology team.¹⁹

The following guidance has been drawn from the Addisons Self-Help Group surgical guidelines and the BNF, and is recommended for dental patients currently on (or within the previous 3 months) steroid therapy over 5 mg prednisolone/day.^35,36,37

To help identify stressful procedures, dental treatment can be classified in the following manner (Table 6).³⁷

Conclusion

Although AC in the dental setting is rare, appropriate management of patients on long-term steroid medication and with primary adrenal insufficiency is paramount. Controversy remains on the peri-operative use of glucocorticoid therapy; however, understanding their physiological role in stress management has hopefully enabled the reader to understand its benefits. Management of the patient should be taken at an individual level, and so deviation from guidance may be necessary. This should only be undertaken following advice from the patient's specialist or prescribing clinician, and following documented discussion with the patient. It is the authors' opinion that there is limited and conflicting evidence at this time in the national guidance for steroid cover in dental procedures. The most up-to-date guidance is provided through the Addison's Clinical Advisory Panels Surgical Guidelines, as the BNF do not provide specific guidance for dental procedures. It would be of interest for dental practitioners for dentists and endocrinologists to review the multitude of guidelines and provide up-to-date national guidance.