David H. P. Streeten, MB, DPhil, Department of Medicine, State University of New York Health Science Center, 750 E Adams St, Syracuse, NY 13210
Fatigue is a prominent accompaniment of a wide range of disorders, including acute or chronic infections, end-stage neoplasia, renal insufficiency, congestive heart failure, and some psychiatric illnesses. It has been speculated that the severe fatigue associated with neurocirculatory asthenia, termed irritable heart syndrome by Da Costa1 and soldier's heart by Lewis2 during World War I, were early descriptions of the symptoms of orthostatic hypotension.3 The common experience of severe fatigue after prolonged, exhausting physical labor or exercise and the muscular symptoms that sometimes accompany chronic fatigue syndrome (CFS) have stimulated research on the possible role of muscular disorders in its causation, but with unconvincing results. And, of course, a viral origin has been commonly considered to be a likely cause of chronic fatigue for many years.
In a careful study comparing patients who had all the features of CFS with age-matched controls, Demitrack et al4 found statistically significant evidence of subnormal urinary-free cortisol excretion, reduced basal evening plasma cortisol concentrations, and attenuation of the integrated corticotropin response to corticotropin-releasing hormone in patients with fatigue. The findings suggested that subnormal cortisol secretion resulting from impaired activation of the hypothalamic–pituitary adrenal axis might cause CFS. Acceptance of this hypothesis was not difficult for endocrinologists familiar with the symptoms of patients with untreated Addison disease, many of whom are characteristically exhausted.
In this issue of THE JOURNAL, McKenzie and colleagues5 (and some of the same authors of the previous study4) present interesting new data on the pathogenesis of CFS. The 70 patients with CFS in this study differed from patients in the previous study4 in having no pretreatment evidence of subnormal urinary-free cortisol excretion or serum cortisol concentrations before or after corticotropin administration. Despite these differences, McKenzie et al5 found that supplementation with small daily doses of hydrocortisone (ie, 20-30 mg at about 8 AM and 5 mg at about 2 PM for 12 weeks) resulted in slight, but consistent, improvement compared with placebo-treated controls in their Wellness scores but without evidence of significant improvement in other self-rating scales. These changes that resulted from the administration of a dose of hydrocortisone that would have been expected to result in rapid and dramatic clinical improvement in patients with Addison disease or hypocortisolism secondary to hypopituitarism were disappointingly modest. The findings appear to confirm the pretreatment steroid measurements that showed no evidence of significant hypocortisolism in the study group as a whole. Because the administered hydrocortisone induced mild suppression of the hypothalamic–pituitary–adrenal axis and resulted in only slight symptomatic improvement, the authors appropriately conclude that their regimen or comparable doses of other glucocorticoids should not be used for prolonged treatment of CFS.
In 1992, Streeten and Anderson6 reported that the most common and most distressing symptom associated in 6 of 7 patients with a newly recognized form of orthostatic hypotensiona delayed form evident only after standing for more than 10 minuteswas severe fatigue that improved by reducing the orthostatic hypotension with fludrocortisone acetate. Subsequently, Rowe et al7 showed that 7 adolescents and 22 of 23 adults with carefully documented features of CFS manifested orthostatic hypotension when tilted head up at 70°, with or often without the concomitant administration of isoproterenol hydrochloride.8 Several of these patients experienced improvement in both orthostatic hypotension and fatigue when they subsequently were treated with fludrocortisone. Streeten et al9 also showed the presence of delayed orthostatic hypotension in 27 of 33 patients with CFS, 93% of whom also had a subnormal circulating red blood cell mass. Symptomatic improvement occurred in 13 of 14 patients when treated in a pilot study either with fludrocortisone alone (n=7) or in 6 of the 7 nonresponders to fludrocortisone alone, during treatment with erythropoietin together with fludrocortisone.9 These findings suggested, as a working hypothesis, that the combination of delayed orthostatic hypotension (caused by demonstrably excessive orthostatic pooling of blood in the lower limbs) associated with reduced circulating erythrocyte mass was causing fatigue in some patients by reducing cerebral oxygenation.
Perhaps the most reasonable conclusion from the evidence to date is that chronic fatigue may have a variety of causes and pathogeneses. In patients with CFS, the cause might include dysfunction of the hypothalamic–pituitary–adrenal axis and hypocortisolism (as in the series by Demitrack et al4) or an infectious agent (as has been suggested during epidemics of chronic fatigue10). The symptoms in many of these disorders might be mediated by orthostatic hypotension6-9 and reduced red blood cell mass.9 Whether or not this hypothesis can be confirmed requires further studies. However, it is inappropriate to consider that CFS is a manifestation of mental disorder unless repeated measurements with the patient both in recumbency and after standing or tilt testing have shown that blood pressure and heart rate are consistently normal. These measurements are labor intensive and expensive but probably are not unreasonable because virtually every type of work and lifestyle requires the capacity to maintain the upright posture for prolonged periods, often for at least 6 hours, without experiencing a symptomatic decrease in blood pressure.
Understanding the nature of chronic fatigue and identifying a specific cause are substantial challenges for clinicians and researchers. Even with the incremental knowledge gained from the study by McKenzie et al,5 an effective and safe treatment remains unavailable. Further studies are needed to unravel the pathophysiologic mechanism of chronic fatigue and to find therapies to effectively ameliorate the debilitating symptoms that accompany this complex disorder.
From the State University of New York Health Science Center, Syracuse.
Reprints: David H. P. Streeten, MB, DPhil, Department of Medicine, State University of New York Health Science Center, 750 E Adams St, Syracuse, NY 13210. Editorials represent the opinions of the authors and The Journal and not those of the American Medical Association
1. Da Costa JM. On irritable heart: a clinical study of a form of functional cardiac disorder and its consequences. Am J Med Sci. 1871;61:17-52.
2. Lewis T. The Soldier's Heart and the Effort Syndrome. London, England: Shaw & Sons; 1919.
3. Streeten DHP. Orthostatic Disorders of the Circulation. New York, NY: Plenum; 1987.
4. Demitrack MA, Dale JK, Straus SE, et al. Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. J Clin Endocrinol Metab. 1991;73:1224-1234. MEDLINE
5. McKenzie R, O'Fallon A, Dale J, et al. Low-dose hydrocortisone for treatment of chronic fatigue syndrome: a randomized controlled trial. JAMA. 1998;280:1061-1066. MEDLINE
6. Streeten DHP, Anderson GH. Delayed orthostatic hypotension. Arch Intern Med. 1992;152:1066-1072. MEDLINE
7. Rowe PC, Bou-Holaigah I, Kan JS, Calkins H. Is neurally mediated hypotension an unrecognized cause of chronic fatigue? Lancet. 1995;345:623-624. MEDLINE
8. Bou Holaigah I, Rowe PC, Kan J, Calkins H. The relationship between neurally mediated hypotension and the chronic fatigue syndrome. JAMA. 1995;274:961-967. MEDLINE
9. Streeten DHP, Bell DS, Thomas FD. Studies of the pathogenesis and treatment of the chronic fatigue syndrome. Clin Auton Res. 1997;7:237-238.
10. Medical Staff of the Royal Free Hospital. An outbreak of encephalomyelitis in the Royal Free Hospital Group, London, 1955. BMJ. 1957;2:895-904.
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