This is a 15 year old male with a PMH of steroid-dependent asthma who presents with a chief complaint of "always feeling tired and weak". Since the age of 7 he has taken inhaled bronchodilators, and for the last 4 years has used high doses of inhaled steroids. During the last 10 months, he required hospitalized twice for status asthmaticus, during which he was given IV and oral corticosteroid bursts. In addition, he has been taking daily oral steroids for the last 5 months. Review of symptoms is significant for a weight gain of 15 kg in the last 3 months, an increased incidence of recent "colds", and the observation by his mother that he seems not to be growing as quickly as his siblings did at this age. His mother also wants to know why, if her son is getting "steroids", he looks as he does rather than "all the athletes on TV who are using steroids".
Exam: VS T 37.3, P 88, RR 14, BP 145/98. Height is at the 10% percentile, and weight in the 50% percentile. He appears tired but in NAD. His visual fields are full. He has severe acne, truncal obesity and a "moon facies". His extremities show several small bruises, muscle wasting with 4/5 weakness, but no areas of hyperpigmentation were seen. There are two areas of poorly healing wounds on his left arm from a fall 3 weeks ago.
Labs: CBC of 14,000 with 1% eosinophils, 2% monocytes, 68% neutrophils, and 29% lymphocytes. Sodium 149, potassium 3.3, chloride 96, bicarbonate 28.5, glucose 110. Cortisol levels were slightly elevated with no diurnal variation.
Given the patient's history, the diagnosis of iatrogenic Cushing's syndrome is made. The patient is weaned off corticosteroid treatment over a period of 5 weeks. His Cushingoid features resolve and his height approaches the 40th percentile. An ophthalmology referral for a subsequent decrease in his vision identifies posterior subcapsular cataracts from his corticosteroid treatment, which are stable but do not resolve.
Corticosteroids are four-ringed steroid hormones produced by the adrenal cortex, with their common biochemical precursor being cholesterol. The corticosteroids are comprised of two major physiological groups: the glucocorticoids and the mineralocorticoids. However, the term "corticosteroids" is generally used to refer to glucocorticoids.
Mineralocorticoids, mainly aldosterone, influence electrolyte balance, and by consequence, intravascular volume and blood pressure. Glucocorticoids are named for their effect on carbohydrate metabolism, but they also have many other effects. One of their most important uses clinically is their complex effect on the immune system. Cortisol is the main physiologic glucocorticoid. Cortisol is called hydrocortisone when it is used pharmacologically. Androgens of the adrenal cortex affect the growth spurt seen in childhood and are responsible for secondary sexual characteristics. It is important to remember that these compounds are chemically similar, and there are clinically important areas of overlap seen in the effects of corticosteroids among these three groups; i.e., some glucocorticoids will have some mineralocorticoid effects, and vice versa.
The adrenal cortex has three layers (GFR): zona glomerulosa, zona fasciculata, zona reticularis, which are responsible for mineralocorticoids, cortisol, and androgenic steroids (salt, sugar, sex), respectively. Cortisol is also produced to some degree in the zona reticularis. Adrenal function is covered in the chapter on adrenal disorders. This chapter will focus on glucocorticoid corticosteroids.
Once corticosteroids are released from the adrenal cortex or absorbed in the body, 90% are bound to plasma proteins, the main two being corticosteroid-binding globulin (CBG) and albumin (1). Once the glucocorticoid is freed from its binding in the plasma by albumin or CBG, it crosses into the cytoplasm by simple diffusion to bind to the glucocorticoid receptor. In the cytoplasm, a glucocorticoid receptor is found in its inactive form bound to various heat-shock proteins. The heat-shock proteins dissociate, and the glucocorticoid-receptor dimer enters the cell nucleus. Short DNA sequences, called glucocorticoid response elements, interact with the glucocorticoid-receptor complex, and this regulates gene transcription by RNA polymerase II and associated transcription factors. The mRNA that is produced is ultimately exported to the cytoplasm for protein production and the final cellular response. Enzyme activity increased by cortisol results in an increase in providing carbon precursors (transaminases, etc.), conversion of pyruvate to glycogen (pyruvate carboxylase, glycogen synthetase, etc.), release of glucose (glucose-6-phosphatase) and disposal of ammonia liberated from urea cycle amino acids (arginine synthetase, argininosuccinase, etc.) (2). This whole process may take several hours for a response to be seen after corticosteroids are given.
In regards to the immune system, cortisol decreases the availability of arachidonic acid, a precursor to many of the inflammatory immune mediators, such as leukotrienes, prostaglandins, and thromboxanes. Cortisol has these effects by inducing the synthesis of a phosphoprotein called lipocortin that inhibits the activity of phospholipase A2. This decreases the synthesis of phosphatidyl choline to arachidonic acid. In addition, cortisol decreases the expression of the gene for cyclooxygenase 2 (which is involved in the production of leukotrienes and thromboxanes) and nitric oxide synthase (that decreases the production of nitric oxide that limits vasodilatation) (2). Corticosteroids are metabolized by the liver and made water soluble so that they may be excreted by the kidneys (1).
The fetal adrenal cortex has two zones, an outer definitive zone that is mainly responsible for glucocorticoid and mineralocorticoid synthesis, and a fetal zone which makes androgenic precursors used by the placenta. At one year of age, the fetal zone has involuted completely, and the definitive zone enlarges. The zona glomerulosa and zona fasciculata are not fully differentiated until age 3, and the zona reticularis may not be fully formed until age 15. At birth, the adrenal glands weigh 8-9 grams, which is twice the size of adult adrenal glands (3). High levels of cortisol may be seen in the first few hours of life, due to the high stress of birth and possibly due to increased levels crossing the placenta. Cortisol changes the fetal digestive pattern to the digestive enzyme capacity of an adult, allowing the newborn to use disaccharides present in milk (2). Cortisol prepares the fetal lung for breathing air by accelerating the rate of alveolar development and thinning of lung septa, and increasing pulmonary surfactant production by increasing the activity of phosphatidyl acid phosphatase and choline phosphotransferase. Betamethasone (a corticosteroid) is given clinically to mothers in premature labor to accelerate fetal lung maturation to reduce the severity of neonatal respiratory distress syndrome. Case reports of newborns with cleft palate, neonatal cataracts, growth retardation, and adrenal suppression have been reported in maternal corticosteroid use (4).
The use of inhaled corticosteroids at recommended doses in childhood does not have a substantial measurable effect on bone mineral density, ocular toxicity, or suppression of the HPA (hypothalamic pituitary adrenal) axis in childhood (5). Studies of inhaled corticosteroids on vertical growth have produced conflicting results. Its effects from childhood to adulthood are not known with certainty (4).
The various steroid compounds have differences in their glucocorticoid and mineralocorticoid activity which are related to their chemical structures, altering their affinities for the mineralocorticoids and glucocorticoids receptors. These structural changes also affect metabolism of the hormones by the liver, fat, or other tissues, its solubility and binding to plasma proteins, its ability to be absorbed, and its excretion. Clinically, these affect the potency and duration of the corticosteroid. For example, if a double bond is placed in the 1,2 position of ring A, then a four-fold increase in glucocorticoid activity is seen with slower metabolism (longer duration) compared to hydrocortisone. This is the case with prednisolone and prednisone. Another example is fluorination at the 9-alpha position on ring B. This increases activity with the glucocorticoid receptor 10-fold, but also increases the mineralocorticoid activity by 125-fold, allowing these to be used as mineralocorticoids at small doses but with little to no glucocorticoid activity at the small doses used. If substitutions are made at C16 on ring D with the 9-alpha fluoro derivatives, then these compounds have marked glucocorticoid activity and virtually no mineralocorticoid activity (triamcinolone, dexamethasone, betamethasone) (1). Cortisone and prednisone are synthetic corticosteroids that require enzymatic reduction by the liver before becoming biologically active. In cases of severe hepatic failure, hydrocortisone and prednisolone should be used, since they do not require this enzymatic activation.
Hydrocortisone, and its synthetic analogs, are effective when given by mouth. Esters of hydrocortisone are more water-soluble and can be given intravenously for quicker and higher concentrations in the body. Glucocorticoids applied topically over the skin can be absorbed systemically with effects on the HPA axis if administration is prolonged or when high potency corticosteroids are used topically over large areas of skin.
Besides being classified by their mineralocorticoid and glucocorticoid relative potencies, corticosteroids can be classified by their duration of action. Short-acting glucocorticoids include cortisol (hydrocortisone) and cortisone. Intermediate-duration glucocorticoids include prednisone, prednisolone, triamcinolone, and methylprednisolone. Long-acting glucocorticoids include dexamethasone and betamethasone. The latter have very high glucocorticoid potencies and very little mineralocorticoid activity.
The table below summarizes glucocorticoid potency and duration. Substitutions and dose equivalencies can be made based on these values.
Glucocorticoid potency equivalence (7):
When used pharmacologically (i.e., higher than physiologic levels), glucocorticoids have profound effects on inflammation and the immune response of lymphocytes. These two processes are linked because both involve leukocyte function. Glucocorticoids, as mentioned above, inhibit phospholipase and cyclooxygenase, limiting the release and production of prostaglandins, thromboxanes, and leukotrienes by mast cells, basophils, and eosinophils. By inhibiting leukotrienes, neutrophil phagocytosis and bacterial function are decreased. Glucocorticoids decrease extravasation of leukocytes and also diminish the secretion of lipolytic and proteolytic enzymes, so that fibrosis is reduced (1). In this way, glucocorticoids can be clinically used to modify (suppress) the inflammatory response. These therapeutic effects have a physiologic basis. Many immune mediators, such as IL-1, IL-6 and TNF-alpha, stimulate the HPA axis during times of stress, increasing glucocorticoids and thus causing a decrease in the immune response.
Glucocorticoids are used in physiologic doses to treat adrenal insufficiency and in pharmacological doses to treat inflammatory and autoimmune conditions. Given that cortisol levels can rise 10-fold in times of stress, high-dose corticosteroids may have a beneficial physiologic effect on the immune system. If the many immune mediators are unopposed by corticosteroids in times of stress, decreased vascular tone and cardiovascular collapse can occur. This important physiologic immune-modulating effect protects the body from an unchecked and full-blown inflammatory response that can have life-threatening consequences (1). Continued use of pharmacological doses can have other adverse effects, such as increasing susceptibility to various bacterial, viral, and fungal infections, permitting their dissemination. Corticosteroid use is contraindicated in patients with tuberculosis, and they must be used with extreme caution with ophthalmic herpes simplex infections. Hypertension, electrolyte and fluid abnormalities, osteoporosis, fat redistribution, acne, hirsutism, and myopathy (among others) can all develop with pharmacologic does of corticosteroids, especially when used over a long period.
Giving a patient glucocorticoids, also affects the amount of different immune cells found in the peripheral blood. The leukocyte count shows a polymorphonuclear leukocytosis (increased WBC count due to increased neutrophils which can be greater than 11,000) with lymphopenia (B and T cells), basopenia, a decreased monocyte count, and eosinopenia in four to six hours after a single dose of hydrocortisone. Neutrophils are increased due to demargination from vascular walls and increased release from the bone marrow. Lymphocytes, basophils, monocytes, and eosinophils are redistributed away from the periphery (1). Glucocorticoids can be used to treat various lymphoid malignancies, either due to being directly toxic to these cells or by inducing apoptosis (programmed cell death).
The acquired or adaptive immune system involves two main parts, cellular immunity and humoral immunity. Cellular immunity is manifested by cytotoxic T cells and natural killer cells involved in protection against intracellular bacteria, protozoa, fungi, and certain viruses. Humoral immunity provides protection against parasites, extracellular bacteria, soluble toxins and allergens, and certain viruses. It involves the production of antibody by B cells. These two systems are controlled by different types of helper T cells. Th1 cells, upon stimulation by IL-12, IFN-delta (among others) from antigen presenting cells (APC), causes a cellular immune response. Th2 cells, upon stimulation by IL4, cause a humoral response. These two systems are related, and an increase in IL-12, will inhibit IL-4 production, shifting the immune response to a mainly Th1, and thus a cellular immune response. Physiologic levels of glucocorticoids cause an increase in humoral immunity, and a decrease in cellular immunity. This effect is mainly due to a glucocorticoid-induced inhibition of IL-12 secretion by APC and IL-12 responsiveness in Th1 cells. This inhibition of IL-12 frees IL-4 to have a more unopposed effect, triggering an enhanced humoral response (6).
Clinically, this decrease in cellular immunity has many important effects. Stress, and the subsequent physiologic increase in glucocorticoids and the Th2 shift, alters an individual's response to infection and autoimmune diseases. Cellular immunity is important in mycobacterial infections and HIV, correlating with the observation that these two diseases may be accelerated with stress and an increase in cortisol. Autoimmune diseases, although extremely complex in their pathophysiological mechanisms, can be thought of as involving mainly Th1 and Th2 mechanisms. Rheumatoid arthritis, multiple sclerosis, type I diabetes, and Crohn's disease are thought to be due to a hyperresponsive Th1 response, with excess IL-12 and TNF-alpha production. Women in their third trimester of pregnancy have increased levels of cortisol, which favors a Th2 response, and a expected remission of these diseases are seen during this time of pregnancy. In addition, decreased stress in the postpartum period or the stopping of glucocorticoid therapy can cause a worsening of these conditions. Th2 driven diseases, such as systemic lupus erythematous, can become worse during stress and pregnancy, when cortisol causes an increased Th2 response (6).
Glucocorticoids induce gluconeogenesis and they have catabolic effects on the periphery which supplies the liver with the amino acids and glycerol needed for gluconeogenesis. Glucocorticoids also decrease glucose uptake in adipose tissue, most likely by moving glucose transporters from the plasma membrane to an intracellular location. This can be thought of as protecting glucose-dependent tissues such as the brain and the heart from starvation during stress. Thus, under prolonged high levels of glucocorticoids, lymphoid tissue, muscle, fat, bone, and skin undergo wasting. This can lead to Cushing's syndrome, with a redistribution of fat from the periphery to the back of the neck (buffalo hump), face (moon facies), and supraclavicular area with less fat in the periphery. One hypothesis to this redistribution is that adipose cells in the neck, face, and supraclavicular area are sensitive to insulin, so the glucocorticoid induced hypoglycemia leads to increased fat deposition in these areas. The peripheral tissues are less sensitive to insulin and respond mainly to the glucocorticoid-induced lipolysis.
Corticosteroids are required for permissive contraction of skeletal muscle. Patients with Addison's disease frequently have fatigue and weakness as symptoms, which may be partly due to vascular insufficiency. Chronic use of corticosteroids can cause skeletal muscle wasting, called steroid myopathy.
Corticosteroids can have direct effects on a patient's mood and behavior. Patient's with Addison's disease can show psychosis, apathy, depression, and irritability. Glucocorticoid administration can have a stimulatory affect, with mood elation, euphoria, insomnia, restlessness, and increased motor activity. These effects are thought to be due to corticosteroidís involvement in the regulation of neuronal activity (neurosteroids).
The most dangerous and life threatening complication of stopping corticosteroid therapy is acute adrenal insufficiency due to the HPA axis being suppressed by exogenous corticosteroids, disabling its ability to endogenously produce corticosteroids in sufficient quantities. By withdrawing corticosteroids, the so-called corticosteroid withdrawal syndrome can lead to cardiovascular collapse due to the loss of cardiovascular tone, with hypotension, shock, and death. Other symptoms of this syndrome include malaise, anorexia, headache, lethargy, nausea, and fever. Hypoglycemia and hyponatremia may be present. This should be considered in patients who have been given supraphysiologic (i.e., pharmacologic) doses of corticosteroids (e.g., a course of prednisone) in the previous year. Patients taking glucocorticoid therapy for 7-10 days can safely be discontinued abruptly. Those on longer therapy need to be tapered, with a 25% reduction in the previous weekly level usually recommended, although patients need to be followed clinically for signs of withdrawal (3). Once a physiological dose is achieved (8-10 mg per square meter body surface area per day) and the patient is stable, the dosage can be decreased to 4-5 mg per square meter per day for 4-6 weeks to allow the adrenal axis to recover. Most patients recover their HPA axis within several weeks, although there is wide variation and some may take a year or longer to recover fully, especially in the physiological response of the HPA to stress. Stress doses of glucocorticoids, usually 3-10 times the physiological replacement, are recommended if a physiologically stressful event (such as surgery) is encountered, for patients receiving chronic or long-term glucocorticoid therapy or for those who have been recently withdrawn from corticosteroids. A further problem of withdrawal can be a flare-up of the disease for which the corticosteroids were originally given.
Other complications or corticosteroids include Cushing's syndrome, growth retardation, the development of posterior subcapsular cataract formation, and advanced bone necrosis. Complications are unlikely if given for less than 2 weeks with moderate doses. Most side-effects of corticosteroids resolve with the exception of the formation of cataracts, which are permanent.
1. Which of the following is not a corticosteroid:
. . . . . a. cortisol
. . . . . b. aldosterone
. . . . . c. adrenal androgens
. . . . . d. norepinephrine
2. Glucocorticoids that are intermediate-potency include
. . . . . a. prednisone
. . . . . b. prednisolone
. . . . . c. triamcinolone
. . . . . d. dexamethasone
. . . . . e. a, b, and c
3. Immune system cells that are increased in the peripheral circulation after corticosteroid administration are
. . . . . a. neutrophils
. . . . . b. eosinophils
. . . . . c. lymphocytes
. . . . . d. monocytes
4. Safely tapering steroids in patient taking oral steroids for more than 10 days involves
. . . . . a. stopping steroid administration all at once
. . . . . b. changing a long-acting glucocorticoid to a short-acting glucocorticoid
. . . . . c. reducing previous weekly levels 10% with no clinical follow-up needed
. . . . . d. reducing previous weekly levels 25% with clinical follow-up
5. Glucocorticoids induce a Th2 shift by
. . . . . a. decreasing IL-12 production by antigen presenting cells, which allows an increase in IL-4 effects and thus more humoral immunity
. . . . . b. increasing IL-12 production by antigen presenting cells, which allows for a decrease in IL-4 and thus more humoral immunity
. . . . . c. glucocorticoids induce a Th1 shift
. . . . . d. none of the above
6. Glucocorticoids do NOT reduce inflammation by
. . . . . a. inhibiting phospholipase and production of arachidonic acid
. . . . . b. inhibiting cyclooxygenase and production of prostaglandins and thromboxanes from arachidonic acid
. . . . . c. decreasing the levels of neutrophils in the peripheral blood
. . . . . d. inhibiting leukotriene action and thus neutrophil function
. . . . . e. decreasing production of nitric oxide by inhibiting nitric oxide synthase
7. A physician orders 40 mg of IV methylprednisolone for a 20 kg patient (2 mg/kg) with status asthmaticus. The hospital pharmacy notifies the physician that IV methylprednisolone is not currently available and is on back order. Utilizing corticosteroid potencies, which of the following are approximate glucocorticoid equivalents?
. . . . . a. Dexamethasone 4 mg (0.2 mg/kg)
. . . . . b. Hydrocortisone 200 mg (10 mg/kg)
. . . . . c. Prednisone 40 mg (2 mg/kg)
. . . . . d. Dexamethasone 400 mg (20 mg/kg)
8. Explain how corticosteroids could be beneficial in croup and status asthmaticus due to a viral pneumonia. In both instances, a viral infection is causing the problem. Since corticosteroids are potentially immunosuppressive agents, is there a net beneficial or detrimental effect?
1. Schimmer BP, Parker KL. Chapter 60 - Adrenocorticotropic Hormone: Adrenocortical Steroids and their Synthetic Analogs; Inhibitors of the Synthesis and Actions of Adrenocortical Hormones. In: Hardman JG, Limbird LE, Gilman AG (eds). Goodman and Gilman's the Pharmacological Basis of Therapeutics, tenth edition. 2001, New York: McGraw-Hill, pp. 1649-1677.
2. Berne MB, Levy MN. Physiology, fourth edition. 1998, St. Louis, Missouri: Mosby, Inc., pp. 930-964.
3. Miller WL. Chapter 21 - The Adrenal Cortex and its Disorders. In: Brook CGD, Hindmarsh PC (eds). Clinical Pediatric Endocrinology, fourth edition. 2001, Oxford, England: Blackwell Science Ltd., pp. 321-376.
4. Coustan DR, Mochizuki TK. Handbook for Prescribing Medications During Pregnancy, third edition. 1998, Philadelphia: Lippincott-Raven Publishers, pp. 197-201.
5. National Asthma Education and Prevention Program Science Base Committee and Expert Panel on the Management of Asthma. Long-term management of asthma in children: safety of inhaled corticosteroids. J Allergy Clin Immunol 2002; 110(2):S160-S168.
6. Elenkov IJ, Chrousos GP. Stress hormones, Th1/Th2 patterns, pro/anti-inflammatory cytokines and susceptibility to disease. Trends in Endocrinology and Metabolism, 1999; 10(9):359-368.
7. Liapi C, Chrousos GP. Chapter 41 - Glucocorticoids. In: Yaffe SJ, Aranda JV (eds). Pediatric Pharmacology Therapeutic Principles in Practice, second edition. 1992, Philadelphia: W.B. Saunders Company, pp. 466-475.
Answers to questions
1.d. Norepinephrine is a hormone of the adrenal medulla, not the adrenal cortex. Corticosteroids are by definition hormones of the adrenal cortex.
2.d. Dexamethasone is a high-potency, long-acting glucocorticoid. Prednisone, prednisolone, and triamcinolone are intermediate-potency glucocorticoids.
3.a. Eosinophils, lymphocytes, and monocytes are reduced in the peripheral circulation after corticosteroid administration. Although neutrophil numbers are increased, their bactericidal activity is decreased.
4.d. Safely tapering corticosteroids in a patient who has taken corticosteroids for more than 10 days, involves reducing the previous week's levels by 25%, and the patient should be monitored clinically for signs of corticosteroid withdrawal (malaise, anorexia, headache, lethargy, nausea, fever, loss of cardiovascular tone, with hypotension, shock, and death) and a worsening of the condition that the corticosteroids were originally given for.
5.a. Th1 cells are stimulated by IL-12 from APC to cause a cellular immune response. Th2 cells, upon stimulation by IL4, cause a humoral response. IL-12 will inhibit IL-4 production as well. Glucocorticoids cause a decrease in IL-12 secretion by APC and IL-12 responsiveness in Th1 cells. This inhibition of IL-12 frees IL-4 to have a more unopposed effect, triggering an enhanced humoral response.
6.c. Glucocorticoids inhibit production of arachidonic acid, prostaglandins, thromboxanes, leukotrienes, and nitric oxide, all of which are involved in the inflammatory response. Neutrophils are increased in the peripheral blood, not decreased.
7. a,b,c are correct. 0.2 mg/kg of dexamethasone would probably be the best answer, although its duration is longer than that of methylprednisolone. This should not be a problem for status asthmaticus. 10 mg/kg of hydrocortisone has equivalent glucocorticoid activity, but it has unnecessary mineralocorticoid activity. 2 mg/kg of prednisone is roughly the same as 2 mg/kg of methylprednisolone, but prednisone would have to be given orally since it cannot be given IV. 20 mg/kg of dexamethasone is clearly an overdose, which results from multiplying by 10 instead of dividing by 10. A good clue would be that dexamethasone comes in 10 mg vials. A 400 mg dose would require 40 vials. This should clearly prompt questioning by pharmacy and nursing staff. Whenever a pediatric dose requires more than one vial, the dose should be questioned.
8. The symptoms of croup and status asthmaticus are largely due to the inflammatory response induced by the viral infection. The virus itself causes less of a problem compared to the body's inflammatory response. Corticosteroids suppress the inflammatory response resulting in less laryngeal and bronchial inflammation. It cannot be assumed that this is true for all viral infections. For example, in viral pharyngitis, the symptoms of a sore throat and nasal congestion may be suppressed with corticosteroids. However, it may cause more harm than good. In the case of croup and status asthmaticus, numerous studies have supported the net benefit of corticosteroids in these two conditions. In bacterial meningitis due to H. flu, a similar benefit has been demonstrated, but for bacterial meningitis due to other organisms and for viral meningitis, the benefit has not been clearly demonstrated.