Systemic side-effects of topical corticosteroids.

With the introduction of topical corticosteroids, a milestone has been achieved in dermatologic therapy; owing to its potent anti-inflammatory and ant proliferative effects, it became possible to treat some hitherto resistant dermatoses. But this magic drug can cause enough mischief if used inappropriately. Children are more susceptible to the systemic adverse effects because of enhanced percutaneous absorption through their tender skin. So, systemic side effects should be kept in mind while prescribing this therapeutically valuable topical medicament.

What was known?

Topical steroids can be absorbed through the skin

Even small doses of potent topical steroids can produce systemic side effects particularly in children and the elderly

Diseased skin has impaired barrier function resulting in enhanced percutaneous absorption and systemic side effects.

Introduction

Topical corticosteroids are one of the most commonly used topical medicines in dermatology. They are in use for more than 50 years. They were first used successfully by Sulzberger and Witten in 1952[1] and their success marked a cornerstone in the history of dermatology. Numerous topical corticosteroids are now available in different preparations, concentrations and potencies. Topical steroids are categorized into seven classes according to their potency. This categorization is based on their vasoconstrictive property. The goal of topical steroid is to deliver therapeutically effective dosage of the drug to the target organ with least possible side effects mainly the systemic ones. The possibility that these drugs could be percutaneously absorbed was considered soon after they came into use, but in several investigations no definitive evidence of such absorption was found. Gradually, however, data have accumulated indicating that the steroids can be absorbed through the skin. Percutaneous absorption of topical steroids depends on a number of factors. The stratum corneum acts as a barrier for percutaneous absorption of drug into systemic circulation.[2] Diseased skin has impaired barrier function resulting in enhanced percutaneous absorption. The horny layer also serves as a reservoir from which drug penetration into the body continues even after a single application.[3] Therefore, even small doses of potent topical steroids can produce systemic side effects like suppression of hypothalamic-pituitary-adrenal axis, iatrogenic Cushing's syndrome and growth retardation in children. Fortunately, these side effects are rare, but may sometimes occur, especially in infants[4] and elderly patients.[5] The existing literature shows conflicting results regarding the systemic side effects, especially about HPA axis suppression following administration of potent topical steroids. This variability of reported adverse effects may be explained by the heterogeneity of patients, the topical steroid studied and the method of assessment used.

Percutaneous Absorption of Topical Steroids

Percutaneous absorption involves passage of the drug through epidermis, dermis, and into the circulation. Topical medicines have poor total absorption and a very slow rate of absorption and topical steroids are no exception to this. Less than 2% of topically applied steroid (hydrocortisone) is absorbed into systemic circulation after single stay on application of more than 1 day.[6]

The stratum corneum acts as the rate-limiting barrier to percutaneous drug absorption. Due to varying thickness of this layer at different body parts, drug penetration also varies at different sites being highest through mucous membrane and scrotal skin and least through palmo-plantar skin.[7] Stratum corneum also acts as a reservoir of topical steroid for up to 5 days. There are two main routes of permeation through stratum corneum: Transepidermal and trans-appendageal. The transepidermal or transcellular pathway is the most important route.[8] Transepidermal transport is governed by Fick's law,[9] i.e., the rate of absorption or flux (J) of any substance across a barrier is proportional to its concentration difference across that barrier. For topically applied drugs, the concentration difference is simply the concentration of drug in the vehicle. Thus,

J = Kp × ΔCs = (Dm × Km)/L × ΔC

where, J is flux, Kp is permeability constant, ΔCs the concentration gradient, Dm is diffusion constant, Km is partition co-efficient and L is length of the diffusion pathway or thickness of the membrane.

Percutaneous toxicity of topical steroids is directly related to percutaneous absorption, so factors governing percutaneous absorption also influence systemic side effects. These factors are:

Age of the patient: Young children have greater surface area to volume ratio and are less able to metabolize the drug quickly and adequately

Body site and area treated: Penetration of the drug correlates inversely with the thickness of the stratum corneum; drug penetration is highest through mucous membrane and scrotal skin and least through palmo-plantar skin

Amount of topical steroid used: Absorption is directly proportional to the mass or concentration of topical steroid applied to the skin up to a critical point

Structure and Potency of the drug: Higher the potency, increased is the chance of systemic side effects. Structural modification alters the lipophilicity and solubility of a molecule and hence its absorption. It also affects the biotransformation of the active molecule

Vehicle of the drug: Vehicle is one of the factors which determine the partition co-efficient, Km and hence percutaneous transport. Solvents such as propylene glycol and ethanol result in an increased permeability after prolonged use.[10] Very occlusive vehicles also lead to enhanced absorption by increasing the hydration of stratum corneum and local temperature[11]

Frequency of application: Repeated application increases the contact period and thus total absorption.

Duration of therapy

Use of occlusion: Occlusion via any means increases the hydration and temperature of stratum corneum and thus enhances drug penetration.[6] Occlusion increases absorption by up to 10 times[12]

Nature of the diseased skin: The skin condition also affects bioavailability. Diseases with impaired barrier function like atopic dermatitis or Netherton syndrome have been associated with enhanced penetration

Coexistent hepatic and renal disease: The glucocorticoids are metabolized mainly in the liver by CYP 3A4 and excreted through kidneys. Concomitant use of other drugs which are potent inhibitors of CYP 3A4 also increases the risk of systemic side effects

Hydration: Hydration of stratum corneum “enlarges” the pathways of diffusion and results in increased permeability[13]

Application of keratolytic agents enhances absorption by damaging the stratum corneum barrier

Dimethyl sulfoxide causes superhydration of stratum corneum with subsequent enhanced permeability[13]

Local hyperemia may cause an increase in flux.[13]

Vigorous rubbing into the skin increases the surface area of skin covered and local blood supply and thus augmenting systemic absorption.

Investigation Protocol

Evaluation of patients suspected to have secondary adrenal failure or HPA axis suppression and Cushing's syndrome may consist of the following tests.

Basal cortisol level measurement

An early morning (8 a.m.) random cortisol is the simplest diagnostic test, but is of limited value. Values below 110 nmol/L (4 μg/dL) are consistent with HPA axis suppression whereas, values between 110 and 469 nanomol/L (4 and 17 μg/dL) are inconclusive.[14] For confirmation, this test is usually substantiated by one of the standard stimulation tests

Midnight or nocturnal salivary cortisol level

This is an excellent diagnostic tool. This assay is especially useful in patients with hypoalbuminaemia secondary to hepatic impairment and in cirrhosis.[15161718] Inadequate sampling and frequent contamination are limiting factors

ACTH stimulation test

This is the preferred method of detecting adrenal suppression. These are of two types; the conventional one using alpha 1-24 ACTH (Synacthen or cosyntropin) in a dose of 250 μg and the low dose ACTH stimulation test using 1 or 10 μg of Synacthen.[192021] This procedure tests the ability of adrenals to respond to exogenous ACTH. Plasma cortisol levels are obtained at 0, 30 and 60 minutes. Cut-off 30-minute values with 1 μg are <18 to 20 μg/dL in non-stressed patients and <25 μg/dL or an increase of <9 μg/dL from baseline in critically ill patients.[22] This test is unreliable in patients with recent onset of HPA axis suppression or with partial adrenal failure

Insulin tolerance test (ITT)

This test evaluates the entire HPA axis and is capable of assessing partial and recent onset adrenal suppression.[19] The aim of this test is to produce symptomatic hypoglycemia to stimulate cortisol release. This test is limited by the associated risk of hypoglycemic seizures and must be performed under supervision. Here, 0.1 to. 15 units/kg short acting insulin is given intravenously and plasma for glucose and cortisol is obtained at 0, 30 and 60 minutes. The test is considered normal if cortisol ≥497 nmol/with symptomatic hypoglycemia and glucose <2.2 mmol/L

Metyrapone test

This provocative test also examines the status of the entire HPA axis.[19] Metyrapone inhibits the final step in cortisol biosynthesis resulting in increased accumulation of 11-deoxycortisol in plasma in subjects with intact HPA axis function. The advantage of this assay over ITT is its safety and convenience. Here in this test, 30 mg/kg of Metyrapone is given orally at midnight and cortisol and 11-deoxycortisollevels are taken at 8 a.m. on the next day. With normally functioning HPA axis, 11-deoxycortisol will be >200 nmol/L regardless of cortisol level.

Other tests that can be done for screening with less definitive results are:

Random serum cortisol

Serum ACTH levels

24-hour urinary free cortisol.

Systemic Side Effects

In addition to local side effects, prolonged use of topical steroids can cause systemic side effects which are less common than those due to systemic corticosteroids. These occur especially in infants and elderly patients. The documented adverse effects are:

Suppression of the hypothalamic-pituitary-adrenal axis

Iatrogenic Cushing's syndrome

Growth retardation in infants and children

Ocular: Glaucoma and loss of vision

Avascular necrosis of femoral head

Severe disseminated cytomegalovirus infection resulting in death in infants.

Exogenous glucocorticoids even in topical form have suppressive effects on hypothalamic cortisol releasing hormone and pituitary adrenocorticotropic hormone (ACTH). With prolonged use, suppression of HPA axis and adrenal insufficiency with adrenal gland atrophy can occur, and it takes months to recover fully after treatment discontinuation. The increased blood level of glucocorticoids can also induce features of hypercortisolism or iatrogenic Cushing's syndrome such as diastolic hypertension, diabetes, buffalo hump, facio-troncular obesity, hirsutism, striae, telangiectasia, skin fragility etc.

According to the existing literature, over the last 35 years, more than 40 (around 43) cases of iatrogenic Cushing's syndrome have been documented.[23] A majority of them were in children and few were in adults. In the children group, most commonly affected age group was infancy (86%) and the major primary dermatosis was diaper dermatitis followed by psoriasis, burn, non-bullous ichthyosiform erythroderma and skin dryness. In adults, psoriasis was most common indication (71%) followed by intertrigo, eczematous dermatitis, chronic skin dryness and lichen planus. Most commonly used steroid in both the groups was Clobetasol propionate (0.05%) and the other was Betamethasone. The median duration of application was 2.75 months (1-17 months) in children and 18 months (0.3-84 months) in adults. The mean recovery period of HPA axis suppression was 3.49 ± 2.92 months and 3.84 ± 2.51 months in children and adults, respectively.

The use of Clobetasol propionate (0.05%) in a dose of 2g/day can decrease morning cortisol level after a few days[24] and use over 100 g/week or 100-300 g/week can result in features of Cushing's syndrome and symptoms of adrenal insufficiency.[2526] Allenby et al.,[27] in their study found that adrenal suppression was to be expected with use of Clobetasol propionate in a dose of more than 50 g/week. In some studies, it has been shown that even a much less amount of topical steroid can induce systemic adverse effects; this may be due to the use of occlusion.[2328]

Cushing's syndrome was also reported with the use of relatively low potent topical steroid triamcinolone acetonide (0.1%) when used in a dose of 38 g daily under occlusion for around 4 years.[29]

The existing literature regarding HPA axis suppression is somewhat controversial, especially in the case of adults. Some workers have noted normal or clinically insignificant suppression of the HPA axis during treatment with topical steroids.[303132] However, others reported a sustained suppression following discontinuation of treatment.[33] According to Castela et al.,[34] all cases of prolonged HPA axis suppression were due to misuse of the drug, i.e. prolonged daily application over several years on larger body surface area. Transient and reversible reduction of HPA axis function can be observed in up to 48%[35] of patients treated with super potent topical steroid, but is usually not associated with clinical symptoms even with long-term maintenance therapy. In most of the short-term studies, plasma cortisol level was mainly recorded early in the course of therapy; and the value returned to normal with recovery of HPA axis function within weeks suggesting that the restoration of epidermal barrier function resulted in reduced percutaneous absorption.

The reported variability of HPA axis status with topical corticosteroid therapy may be because of the heterogeneity in study groups and topical steroids studied and method of assessment used to assay the HPA axis function.

Growth impairment has been reported in an infant treated with betamethasone valerate (0.1%) ointment for three years using 30 gram/week.[36] Excess glucocorticoids leads to short stature due to suppression of GHRH (growth hormone releasing hormone) and GH release from the hypothalamus and pituitary respectively.[37]

Turpeinen et al., described a case of osteonecrosis of femoral head following application of clobetasol propionate in a patient of atopic dermatitis.[38] Osteoporosis is a serious side effect of systemic and inhaled corticosteroid therapy, but some loss of bone mineral density is also seen with the use of topical corticosteroids in psoriasis.[3940] The bone loss caused by glucocorticoids is trabecular in nature affecting vertebrae and ribs of the axial skeleton.

Prolonged use of topical steroids on the eyelid can induce open-angle glaucoma and cataract from transpalpebraltarsal penetration.[41]

Death due to disseminated cytomegalovirus infection in two infants is the dreaded complication reported yet. In both the cases, clobetasol propionate was the culprit agent.[42]

What is new?

A systematic compilation of systemic side effects of topical corticosteroids to increase awareness among dermatologists

Some rare systemic side effects have been discussed.