Morphologic changes

Redistribution of adipose tissue is a common effect associated with prolonged corticosteroid treatment ( Table 1 ). These changes are known as cushingoid changes, and include truncal obesity, facial adipose tissue referred to as moon facies, and dorsocervical adipose tissue referred to as buffalo hump. The rate at which this occurs is variable. It has been reported to occur in 15% of patients in less than 3 months’ time, with doses equivalent to 10 to 30 mg of prednisone per day. A different study found that 13% of patients taking up to 12 mg of prednisone daily for more than 60 days developed moon facies, with up to 66% of the patients demonstrating this complication from corticosteroid use over 5 years. A meta-analysis of randomized controlled trials found that these changes occur more frequently in patients receiving steroids than in patients receiving placebos. Higher doses and longer duration of corticosteroid use seem to increase the frequency of adipose tissue redistribution. Patients taking daily prednisone demonstrated adipose redistribution or corticosteroid-induced lipodystrophy at incidences of 61%, 65%, and 69% at 3, 6, and 12 months, respectively, with mean doses of 32 mg, 19 mg, and 11 mg at the respective time points. This study further demonstrated that the risk was higher in women, patients less than 50 years of age, and patients with either a high initial body mass index or a high calorie intake.

Hyperglycemia

Corticosteroids increase blood sugar levels by increasing hepatic gluconeogenesis and by decreasing glucose uptake in peripheral tissues. Corticosteroids stimulate proteolysis, promote the release of gluconeogenesis-stimulating enzymes, and inhibit adipose and muscle tissue glucose uptake. Furthermore, acute exposure to corticosteroids causes insulin resistance by decreasing the ability of adipocytes and hepatocytes to bind insulin. This effect can occur within 12 hours of beginning therapy, although it has been found to decrease with prolonged corticosteroid use. Synthetic corticosteroids such as prednisone and dexamethasone are 4 and 30 times more potent, respectively, than natural corticosteroids such as hydrocortisone at decreasing carbohydrate tolerance.

Correlations have also been made to steroid dose and the development of diabetes, with daily and cumulative dose likely independent risk factors. Several studies have demonstrated a statistical correlation between hyperglycemia and exogenous corticosteroid use. On cessation of corticosteroids, the inhibition of glucose uptake and metabolism in peripheral tissues usually returns to normal. Despite their common use, the effect on blood glucose levels and the degree of hyperglycemia caused by steroids have not been clearly elucidated.

Hyperglycemia

Corticosteroids increase blood sugar levels by increasing hepatic gluconeogenesis and by decreasing glucose uptake in peripheral tissues. Corticosteroids stimulate proteolysis, promote the release of gluconeogenesis-stimulating enzymes, and inhibit adipose and muscle tissue glucose uptake. Furthermore, acute exposure to corticosteroids causes insulin resistance by decreasing the ability of adipocytes and hepatocytes to bind insulin. This effect can occur within 12 hours of beginning therapy, although it has been found to decrease with prolonged corticosteroid use. Synthetic corticosteroids such as prednisone and dexamethasone are 4 and 30 times more potent, respectively, than natural corticosteroids such as hydrocortisone at decreasing carbohydrate tolerance.

Correlations have also been made to steroid dose and the development of diabetes, with daily and cumulative dose likely independent risk factors. Several studies have demonstrated a statistical correlation between hyperglycemia and exogenous corticosteroid use. On cessation of corticosteroids, the inhibition of glucose uptake and metabolism in peripheral tissues usually returns to normal. Despite their common use, the effect on blood glucose levels and the degree of hyperglycemia caused by steroids have not been clearly elucidated.

Infection

The mechanism by which corticosteroids decrease inflammation may also lead to immunosuppressive effects. Steroids decrease the peripheral concentration and function of leukocytes. Whereas circulating neutrophils increase as a result of enhanced release from bone marrow and reduced migration from blood vessels, the number of other leukocytes such as lymphocytes, monocytes, basophils, and eosinophils decrease. This decrease in peripheral leukocytes is a result of a migration from the vascular bed to lymphoid tissue. Corticosteroids can further affect neutrophil function by reducing their adherence to vascular endothelium as well as their bactericidal activity. Corticosteroids further inhibit the function of macrophages and other antigen-presenting cells by limiting chemotaxis, phagocytosis, and the release of cytokines such as tumor necrosis factor α and interleukin-1. Corticosteroids have also been shown to decrease the expression of inflammatory mediators such as prostaglandin, leukotriene, and platelet-activating factor, and at higher doses have been shown to inhibit B-cell production of immunoglobulins. The administration of corticosteroids on an alternate days has been shown to reduce their negative impact on leukocyte function.

A meta-analysis by Stuck and colleagues reviewed 71 clinical studies to assess for the relative risk of corticosteroids on the rate of infections. They found that the overall rate of infections was 8.0% in the control group and 12.7% in patients receiving corticosteroids, a statistically significant increase. Their review found that patients who received a daily dose of less than 10 mg per day or a cumulative dose of less than 700 mg of prednisone did not have an increased rate of infectious complications.

A meta-analysis of more than 8700 patients by Conn and Poynard found that bacterial sepsis occurred 1.5 times more frequently in patients using corticosteroids than in those using placebo ( P <.01). The mean daily dose was the equivalent of 35 mg of prednisone and the mean total dose was 2200 mg of prednisone for these patients. Although the disease processes for which the patients are being treated may themselves be independent risk factors for increased infection, few studies in the aforementioned meta-analyses included patients with autoimmune diseases, which are known risk factors for increased infections.

Several studies have demonstrated that patients treated with glucocorticoids are at increased risk for developing invasive fungal infections, pneumocystosis, and viral infections, especially in patients who have undergone bone marrow transplantation. O’Donnell and colleagues retrospectively reviewed 331 allogeneic bone marrow recipients and found that the major risk factor for candidemia or aspergillosis was prednisone treatment (0.5–1 mg/kg/d). None of the 36 cases of systemic fungal infections were in the paranasal sinuses. Several studies from the Fred Hutchinson Cancer Research Center and University of Washington demonstrate an increased risk of invasive mold infections (including Aspergillus and Zygomycetes) as well as an increased risk of death from these infections in bone marrow transplant patients receiving high-dose corticosteroids (≥2 mg/kg/d prednisone or methylprednisolone).

Wound healing

Wound healing occurs in an orderly fashion. The initial response to a surgical injury is an inflammatory reaction in which the wound is invaded by polymorphonuclear leukocytes and lymphocytes. These cells are then replaced by macrophages from circulating blood monocytes. The presence of the macrophages is essential for normal wound healing. Within 48 hours, reepithelialization and angiogenesis occur as part of the proliferation phase, which includes extensive capillary budding and proliferation of fibroblasts in the wound site. Collagen deposition begins within 4 or 5 days, and is responsible for the initial wound strength. Collagen deposition is followed by the formation of covalent bonds and scar remodeling, which leads to additional wound strength and maturation.

Corticosteroids inhibit the natural wound-healing process in several ways. First, they decrease the circulating monocytes, thus decreasing the influx of macrophages. Studies suggest that the reduced number of macrophages may decrease phagocytosis as well as growth factor/cytokine production. In addition, corticosteroids can delay reepithelialization, decrease the fibroblast response, slow capillary proliferation, and inhibit collagen synthesis and wound maturation, ultimately leading to delayed wound healing and decreased tensile strength.

Several topical and systemic agents such as epidermal growth factor, transforming growth factor β, platelet-derived growth factor, and tetrachlorodecaoxygen have been shown to counteract the effect of corticosteroids on wound healing. Systemic agents such as vitamin A and insulinlike growth factor 1 also may counter the impact of corticosteroids on wound healing.

Bone metabolism

The role of steroids in bone loss is well described and may occur through several different mechanisms. First, they cause a negative calcium balance via an anti–vitamin D effect by reducing intestinal calcium absorption and increasing urinary calcium excretion. This negative calcium balance stimulates parathyroid hormone production, which increases osteoclast activity, accelerates bone absorption, and releases calcium into the circulation at the expense of bone mass. In addition, steroids inhibit osteoblast activity, negatively affecting trabecular bone formation. This effect places bones, such as vertebral bodies, femoral necks, and distal radii, at increased risk for fracture.

Corticosteroids also suppress the production of adrenal androgens, decreasing their beneficial effect on bone formation. Prednisone doses higher than 20 mg per day decrease the production of gonadotropin-releasing hormone, which decreases the production of luteinizing hormone, leading to a secondary hypogonadism state. This secondary hypogonadism decreases testosterone production, further decreasing bone formation and increasing bone resorption.

Corticosteroids have been found to cause apoptosis of osteoblasts and osteocytes. This effect has been shown to occur within 1 month of use; however, it slows after 6 to 12 months. A reduction in bone formation based on markers of bone metabolism has been demonstrated with as little as 5 mg of prednisone daily for as short as 2 weeks. van Staa and colleagues found a dose-related reduction in osteocalcin levels, a marker of bone formation, within the first 24 hours of prednisone therapy. This effect was rapidly reversible with cessation of prednisone therapy.

Paglia and colleagues studied bone resorption and formation in 14 elderly men who were placed on courses of prednisone for less than 30 days at a mean cumulative dose of 338 mg of prednisone. The investigators found statistical differences in the steroid group, with significant increases in markers of bone turnover and decreases in markers of bone formation. In addition, osteocalcin levels were inversely correlated with the cumulative dose of prednisone. A second study measured the dose-related changes in serum osteocalcin in patients with asthma on a 12-day course of oral prednisolone with doses increasing every 4 days. They found that after 4 days of 5 mg daily, there were no significant differences in osteocalcin levels; however, a significant decrease was noted after 10 mg, and the levels continued to decrease after daily doses of 20 mg.

The clinical significance of these changes in markers of bone metabolism as they relate to changes in bone mineral density has been debated. A study performed by Laan and colleagues compared bone mineral densities in patients treated with or without corticosteroids for their rheumatoid arthritis. The investigators found that postmenopausal women taking a mean daily dose of 6.8 mg of prednisone (mean cumulative dose was 22.5 g) for a mean duration of 7.9 years (range 1.1–31.9) had a statistically significant decrease in trabecular bone mineral density, cortical bone mineral density, and a statistically significant increase in vertebral deformities compared with patients not using prednisone. Male patients taking a mean daily dose of 7.1 mg of prednisone for a mean duration of 4.2 years (range 0.9–9.2) had no statistically significant difference in bone mineral density or vertebral deformities compared with patients not using prednisone. Although these data conflict with earlier studies, the investigators used quantitative computed tomography, which is more accurate than traditional bone density studies in assessing bone mineral densities. Limitations of this study include insufficient premenopausal women to include for statistical analysis, a relatively small sample size, and the fact that patients receiving prednisone had clinically more severe rheumatoid arthritis, which itself is a risk factor for reduced bone mineral density.

Data are conflicting as to whether daily dose or cumulative dose has a more significant clinical effect on bone density. A meta-analysis by van Staa and colleagues demonstrated a stronger correlation between cumulative steroid dose on bone mineral density than daily dose. Fracture risks have also been shown to increase based on dose, duration, age, gender, and body weight. Several studies have demonstrated that supplemental calcium and vitamin D, as well as bisphosphonates can help reduce the corticosteroid-induced loss of bone mineral density.

Corticosteroid use has also been associated with avascular necrosis or osteonecrosis. This complication has been correlated with cumulative dose, and has been seen primarily in the head of the femur, although other weight-bearing and non–weight-bearing bones can be affected. The exact cause is not fully understood, but is thought to include embolic events in the blood supply, a hyperviscous state of the blood, cellular cytotoxic factors, hypertrophy of marrow fat cells, which increases the pressure in the femoral head, resulting in decreased blood flow, or generation of bone edema, all leading to impaired perfusion of the bone.

A retrospective review of patients treated for osteonecrosis of the femoral head in an orthopedic clinic identified 15 patients who had been treated with a single course of glucocorticoids over a 3-year period, before presentation. All patients were male; 13 had received prednisone, 2 dexamethasone. The mean age was 32.2 years (range 20–41 years), the mean cumulative dose was 850 mg of prednisone (range 290–3300 mg), and the mean duration of therapy was 20.5 days (range 6–39 days). The patient who presented after the lowest cumulative dose of prednisone, 290 mg in 7 days, was one of the latest presenters. He presented with pain 23 months after corticosteroid treatment for poison ivy. The mean time from treatment to symptoms in the study was 16.6 months (range 6–33 months). Another retrospective series of 1352 patients treated with corticosteroids for neurosurgical issues identified 4 cases of avascular necrosis, a risk of 0.03%. The mean age was 26 years (range 21–31 years), the mean cumulative dose was equivalent to 673 mg of prednisone (range 389–990 mg of prednisone equivalents), and the mean duration was 20 days (15–27 days). The time for onset of symptoms in this group ranged from 4 to 27 months, with a mean of 14.5 months.

Ophthalmic

Corticosteroids can have extensive ophthalmic effects, depending on the route of administration. Systemic administration of corticosteroids can lead to cataract formation, increased intraocular pressure, myopia, exophthalmos, papilledema, central serous chorioretinopathy, and subconjunctival hemorrhages. The most commonly encountered ophthalmologic side effects include cataract formation and increased intraocular pressure or glaucoma. The correlation between corticosteroids and posterior subcapsular cataracts was first described in the 1960s, with the incidence dependent on dose and duration of corticosteroid use. Although studies have shown that doses as low as 5 mg of oral prednisone taken for as little as 2 months can lead to cataracts, most report doses of 10 mg or more daily for at least 1 year before the onset of cataract formation. Many causes of steroid-induced cataract formation have been proposed. One theory suggests that steroid molecules bond covalently with the lysine residues of the lens, leading to opacities. Another proposed mechanism states that corticosteroids inhibit the sodium-potassium pump in the lens, leading to an accumulation of water and coagulation of lens proteins.

Increased intraocular pressure can lead to visual field loss, optic disk cupping, and optic nerve atrophy. The correlation between increased intraocular pressure and glaucoma was first identified in the early 1950s. Corticosteroids cause significant increases in intraocular pressure in approximately 5% of patients within the first few weeks of therapy. Eventually, between 18% and 36% of the population will develop at least a moderate (5 mm Hg or greater) increase in pressure with prolonged steroid treatment. Factors associated with a greater risk of increased intraocular pressure induced by corticosteroids include open-angle glaucoma, diabetes mellitus, high myopia, rheumatoid arthritis, hypertension, migraine headaches, and first-degree relatives with open-angle glaucoma. The route of administration seems to play an important role; topical ophthalmic and systemic administration have a high correlation with the incidence of glaucoma. The exact mechanism by which corticosteroids cause glaucoma is unknown. One theory suggests that corticosteroids may have a negative effect on the trabecular meshwork by causing the buildup of proteins such as glycosaminoglycans, fibronectin, elastin, laminin, and collagens or by preventing the appropriate expression of prostaglandins, collagenase, plasminogen activator, and stromelysin, enzymes that help break down outflow obstructions. When the trabecular meshwork does not allow for proper drainage, fluid is retained and pressures increase.