Mark S. Grossman, M.D., F.A.A.P.

Case Report

A 37-year-old female presented to the office with the chief complaint of weight loss. Of note, the patient had a history of asthma, which was controlled for the last few years on the inhaled corticosteroid, fluticasone 440 mcg b.i.d., as well as intermittent inhaled albuterol. In addition, she had been on brief courses of oral prednisone twice in the prior year for asthma exacerbation. Her past medical and family history was unremarkable for any endocrine problems.

On history, the patient had noted an unintentional 10-pound weight loss, from 99 to 89 pounds, over the last month. She denied any recent dieting or excessive exercising, fasting or purging. Her appetite and food intake were relatively unchanged. She did note nausea on two occasions over the last few weeks prior to her visit, but no vomiting, diarrhea or abdominal pain. The patient also complained of increased fatigue and weakness in the form of diminished strength and stamina while caring for her two children, ages two and five. She denied symptoms of fever, dizziness, light-headedness, skin changes or alterations in her menses. She had noted increased emotional lability in the weeks prior to her office visit.

Physical exam revealed a thin female in no acute distress and with appropriate mental status. Her blood pressure was 110/60 supine and 100/70 standing. Her pulse was 70 and regular supine and 85 standing. Her weight was 89 pounds. Her height was 5 feet 3 inches. Skin was warm and smooth without rash or hyperpigmentation. Neck exam showed no thyromegaly. Lungs revealed coarse symmetric breath sounds. Extremities showed no joint swelling or edema. The remainder of the exam was unremarkable.

Labs drawn at the time of the visit revealed normal electrolytes, normal liver assessment tests, and a normal complete blood count. Her TSH was 1.3 µIU/mL, which was within normal limits. Her fasting morning cortisol level was <0.2 µg/dL, which was markedly suppressed. On follow-up visit, additional pituitary function tests consisting of LH, FSH, and estradiol were within normal limits. Additionally, a 24-hour urinary free cortisol obtained was very low at 2.8 µg/24 h Cr, which confirmed the low production of cortisol.

She was taken off her inhaled corticosteroids and placed on a leukotriene inhibitor to control her asthma. Within 4 months, she had gained 12 pounds and her adrenal function had returned as documented by a normal 24-hour urine cortisol measurement. In addition, her asthma remained in good control.

Discussion

Secondary adrenal suppression following chronic use of inhaled steroids for asthma is a relatively infrequent, but potentially significant, clinical condition. Adrenal insufficiency when present can be readily diagnosed and easily treated. If missed, especially with high dose therapy, adrenal crisis can occur during times of significant physiologic stress. The symptoms of weakness, fatigue, weight loss and gastrointestinal complaints are common to many other disorders, so adrenal insufficiency should be considered in their differential diagnosis.

While rarely occurring from natural causes, secondary adrenal insufficiency is most commonly caused by suppression of the hypothalamic-pituitary-adrenal (HPA) axis by exogenous glucocorticoid administration. This leads to inadequate secretion of ACTH and CRH and consequently results in insufficient adrenal cortisol secretion.

In comparison to primary adrenal insufficiency, the clinical presentation of secondary adrenal insufficiency is one of pure glucocorticoid deficiency. Mineralocorticoid secretion is usually normal because it is regulated by the renin-angiotensin system. Therefore, an initial presentation of shock or hypotension is rare. The process is usually gradual, going through an initial stage of partial ACTH deficiency that is evident only in inadequate cortisol responses to stress.¹

The signs and symptoms of clinical presentation depend on the rate and degree of loss of adrenal function and on the degree of physiologic stress. As onset is often insidious and signs and symptoms are often nonspecific, adrenal insufficiency may go undetected until a concurrent illness precipitates a crisis.

The clinical features of secondary adrenal insufficiency are similar to those of primary adrenal insufficiency with two major exceptions. One exception is that hyperpigmentation is absent since plasma ACTH levels are not elevated. Second, dehydration and hypotension is less prominent since mineralocorticoid deficiency does not occur. Weakness, fatigability, myalgias and psychiatric symptoms are as common as in primary adrenal insufficiency indicating that most of these symptoms are caused by glucocorticoid deficiency alone.²

The laboratory findings in secondary adrenal insufficiency are the same as those in primary adrenal insufficiency, except that plasma ACTH levels are not elevated and hyperkalemia does not occur.

The ACTH stimulation test remains the main diagnostic test for both primary and secondary adrenal insufficiency. The ACTH stimulation test is clinically relevant because it accurately reflects the adrenal reserve. Additional advantage includes its ease and broad experience with its use. More recent low-dose ACTH stimulation testing uses only 0.5 µg or 1 µg of ACTH instead of the traditional dose of 250 µg. The rationale of the low-dose ACTH test is that it may have higher sensitivity compared with the traditional test, but experience with this test is still evolving.³

Low cortisol secretion as measured in the spot A.M. plasma cortisol level and 24-hour urinary free cortisol excretion can also be a diagnostic finding.⁴ The A.M. plasma cortisol test is only useful when the cortisol plasma levels fall in the extremes. For example, it is diagnostic of adrenal insufficiency when plasma cortisol is less than 3 µg/dL, and rules out adrenal insufficiency when plasma cortisol is equal to or greater than 20 µg/dL. Unfortunately, in most instances, plasma cortisol falls in between these two extremes and is non-diagnostic. The 24-hour urine free cortisol reflects the integral daily production of cortisol, thus avoiding the circadian variations in plasma cortisol. Its limitation is that it may not reflect the adrenal reserve as accurately as the ACTH stimulation test. Radiologic methods are of little help in establishing the diagnosis of secondary adrenal insufficiency as adrenal atrophy cannot be reliably demonstrated by CT or MRI scan.⁵

As the understanding of the pathophysiology of asthma expands, anti-inflammatory therapy has become an essential key to treatment. Inhaled steroids, in particular, improve control of asthma, allow for a reduction in oral glucocorticoid usage and improve quality of life.⁶ However, the controversy over the safety of inhaled steroids has increased as newer, more potent products become available. Adverse effects are usually limited to oral candidiasis and hoarseness, but may also include the more serious systemic effects of HPA axis suppression and growth retardation as well as increased osteoporosis, skin bruising and cataract risks.⁷ The trend toward the earlier use of inhaled corticosteroids, particularly in children, makes it even more important to understand their potential for producing systemic adverse effects during long-term administration.

A number of factors influence adrenal suppression with inhaled corticosteroids. The compound, dose, frequency of administration and timing of dose all play a role in subsequent actions on the HPA axis. Another key variable is duration of treatment; prior long-term systemic steroid use may play a significant role in adrenal suppression. It is also known that there is significant variability of side effects between individuals in different populations taking a dose of glucocorticoid.¹

Fluticasone propionate has been a particularly well-studied inhaled glucocorticoid. It was felt to be a safer choice due to its low oral bioavailability. Since its release, fluticasone was found to have a topically active anti-inflammatory potency twice that of beclomethasone. The long receptor half-life leads to absorption from the pulmonary bed and systemic bioavailability.⁷ Recent studies have shown that despite only 1% bioavailablity after oral fluticasone, a significant (15%) amount may be absorbed from the lung after treatment with inhaled fluticasone. Another study showed that 1000 mcg of inhaled fluticasone had a systemic effect equivalent to 10 mg of oral prednisolone as measured by suppression of A.M. plasma cortisol.⁸

The clinical relevance of inhaled corticosteroid treatment at a defined dose should be viewed in the context of HPA axis suppression after long-term use. At low to medium doses of inhaled corticosteroids, iatrogenic Cushing's syndrome is absent and only partial inhibition of HPA axis occurs, with essentially no risk of adrenal crisis. At high doses of inhaled corticosteroids, iatrogenic Cushing's syndrome has been reported as well as variable HPA axis suppression with significant inter-patient variability. Because of the risk of impaired pituitary-adrenal response during significant concurrent illness in some patients taking high-doses of inhaled corticosteroids, adults receiving >660 mcg/day and children receiving >400 mcg/day should be considered for treatment with additional systemic glucocorticoids. In addition, all patients with Cushingoid stigmata and/or previously treated with long-term oral steroids should be considered for additional doses of systemic steroids during times of significant physiologic stress.¹

The NIH Guidelines for the Diagnosis and Management of Asthma recommends a stepwise approach for treating asthmatics based on clinical severity, with clinical judgment of patient response being essential to appropriate dosing. This approach emphasizes that medication usage should be titrated to the minimum dose required to maintain control, thus reducing the potential for adverse effect.⁵ In particular, physicians should be keenly aware of the risk for systemic effects in children receiving moderate and high dose therapy, such as adrenal and growth suppression. For children on low dose therapy, it would seem reasonable to perform a growth assessment at every visit and consider adrenal testing if signs of glucocorticoid excess are evident. For children on high dose therapy, it has been suggested that, in addition to growth assessment every 4 to 6 months, either an ACTH stimulation test be done or an A.M. plasma cortisol be drawn 2 months after beginning therapy and periodically thereafter.⁶ If the A.M. cortisol is abnormal or growth is suppressed, anevaluation of the HPA axis with free urine cortisol should be obtained. Evidence of HPA suppression should be handled by gradually decreasing the dose of inhaled steroid and administration of parenteral or oral cortisone supplementation, preferably hydrocortisone, as needed for stress.

Conclusion

Physicians should maintain a high index of suspicion for adrenal suppression in their asthmatic patients on inhaled corticosteroids, who present with non-specific constitutional signs and symptoms. The potential for systemic adverse effects with high dose corticosteroids may be less in the future with the introduction of many nonsteroidal therapies, such as leukotrienes modifiers, inhaled anticholinergic agents and long-acting beta-2 agonists. In addition, especially for the mildly asthmatic child, inhaled cromolyn still has a role in maintenance therapy. In the severe asthmatic, theophylline may permit the use of a lower dose of inhaled corticosteroid when used as an additive therapy.⁹ For those patients who require inhaled steroids for asthmatic control, physicians should use the lowest possible dose of these compounds to control symptoms and perform regular checks for evidence of systemic adverse effects. The latest NIH Guidelines for the Diagnosis and Management of Asthma has an excellent outline on the stepwise approach to managing asthma in adults and children.