Pituitary DOI 10.1007/s11102-006-0408-5
Isolated corticotrophin deficiency Massimiliano Andrioli · Francesca Pecori Giraldi · Francesco Cavagnini
Published online: 30 October 2006 C Springer Science + Business Media, LLC 2006
Abstract Isolated ACTH deficiency (IAD) is a rare disorder, characterized by secondary adrenal insufficiency (AI) with low or absent cortisol production, normal secretion of pituitary hormones other than ACTH and the absence of structural pituitary defects. In adults, IAD may appear after a traumatic injury or a lymphocytic hypophysitis, the latter possibly due to autoimmune etiology. Conversely, a genetic origin may come into play in neonatal or childhood IAD. Patients with IAD usually fare relatively well during unstressed periods until intervening events spark off an acute adrenal crisis presenting with non specific symptoms, such as asthenia, anorexia, unintentional weight loss and tendency towards hypoglycemia. Blood chemistry may reveal mild hypoglycemia, hyponatremia and normal-high potassium levels, mild anemia, lymphocytosis and eosinophilia. Morning serum cortisol below 3 µg/dl are virtually diagnostic for adrenal insufficiency. whereas cortisol values comprised between 5-18 µg/dl require additional investigations: insulin tolerance test (ITT) is considered the gold standard but— when contraindicated—high or low dose-ACTH stimulation test with serum cortisol determination provides a viable alternative. Plasma ACTH concentration and prolonged ACTH infusion test are useful in differential diagnosis between primary and secondary adrenal insufficiency. For some patients with mild, near-to-asymptomatic disease, glucocorticoid replacement therapy may not be required except during stressful events; for symptomatic patients, replacement doses i.e., mean daily dose 20 mg (0.30 mg/kg) M. Andrioli · F. P. Giraldi · F. Cavagnini () Chair of Endocrinology, University of Milan, Ospedale San Luca, Istituto Auxologico Italiano, Milan, Italy e-mail:
[email protected]
hydrocortisone or 25 mg (0.35 mg/kg) cortisone acetate, are usually sufficient. Administration of mineralocorticoids is generally not necessary as their production is maintained. Keywords ACTH deficicency . Hypopituitarism . Hypoglycemia . Hypophysitis Demographics and pathogenesis ACTH deficiency is usually associated with diminished GH, gonadotropin or TSH reserve, in the context of partial or total pituitary insufficiency. Isolated ACTH deficiency (IAD) is a rare disorder, first reported by Steinberg in 1954, characterized by secondary adrenal insufficiency (AI) with low or absent cortisol production, normal secretion of pituitary hormones other than ACTH and the absence of structural pituitary defects [1]. The prevalence of secondary AI, most commonly due to glucocorticoid administration, is much higher than that of primary AI, with an estimate of 150–280 cases per million [2, 3]. IAD accounts for only a small part of secondary AI and the rarity of its occurrence explains the uncertainties in its epidemiology and etiology. In adults, an autoimmune etiology is most often hypothesized, in alternative to traumatic cases. Indeed IAD may appear after a lymphocytic hypophysitis [4], especially in the peripartum period [5]. In support of this hypothesis, antibodies against a 22 kDalton pituitary protein have been detected in patients with IAD or lymphocytic hypophysitis [6, 7]. Post-traumatic ACTH deficiency is usually associated with other pituitary defects; persistent [8] or transient [9] post-traumatic IAD has been described. IAD may also be part of an atypical Sheehan’s syndrome [10], be associated to empty sella [11] and appear after radiation therapy for brain tumor [12].
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Conversely, in neonatal or childhood IAD a genetic origin may be suspected.
Laboratory diagnosis Blood chemistry
Diagnosis Clinical diagnosis IAD has diverse clinical presentations and occasionally, if unrecognized, a fatal course. Clinical findings of IAD are similar to those found in primary AI although usually less severe [13] and excepting cutaneous hyperpigmentation and electrolyte disturbances. Patients with IAD usually fare relatively well during unstressed periods until intervening events spark off an acute adrenal crisis. This serious condition is characterized by extreme fatigue, acute abdominal pain, nausea and vomiting, diarrhea, fever, severe hypotension and hypoglycemia, and, if not promptly recognized, may be irreversible. Patients with IAD usually present with non-specific symptoms, such as asthenia, anorexia, unintentional weight loss and tendency to hypoglycemia. Alabaster-colored skin may contribute to the wan appearance of patients and aid in the distinction between primary and secondary AI. Unlike primary AI, secondary AI is not associated with lack of aldosterone, thus symptoms and signs of mineralocorticoid deficiency (salt-craving, postural hypotension, electrolyte abnormalities) are usually absent. Hyponatremia may occasionally occur as a result of reduced glomerular filtration rate, increased antidiuretic hormone secretion and concomitant hypothyroidism. IAD may present with atypical manifestations, such as flexion contractures of the legs [14] or severe muscle atrophy [15]. Other unusual presentations are pericardial effusion [16], recurrent syncope [17] or cholestatic jaundice [18]. These clinical manifestations, though not typical of AI, seem to be closely related to the hypoadrenal condition because they disappear on steroid replacement therapy. Primary infertility [19], Crohn’s disease [20], myasthenia gravis [21], polycystic kidney disease [22], spinocerebellar ataxia type 3 [23] and benign endocranic hypertension [24] have also been reported in conjunction with IAD. Lastly, IAD is not infrequent in chronic alcoholism [25, 26] and, as in patients with the above-mentioned disorders, should be considered if more typical hypoadrenal symptoms are present. Likewise, IAD should also be kept in mind in patients with other autoimmune diseases: IAD due to lymphocytic hypophysitis has often been described associated with autoimmune hypothyroidism [27, 28] and, occasionally, with Graves’ disease [29], type 1 diabetes [30] and polyglandular autoimmune failure [31]. Neonatal and childhood IAD will be discussed separately (see below).
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Blood chemistry may reveal mild hypoglycemia, hyponatremia and normal-high potassium levels, mild anemia, lymphocytosis and eosinophilia, all signs of AI. Rarely, glucocorticoid deficiency can result in hypercalcemia, due to increased intestinal absorption and decreased renal excretion of calcium [32–35]. TSH is usually mildly elevated, as the physiological inhibitory effect of cortisol on TSH is absent [36]. Endocrine parametres Diagnosis of adrenal insufficiency Morning serum cortisol is usually the first step in the diagnostic work-up, although this test is indicative only if values are extremely low, i.e., adrenal insufficiency is near to certain with values below 3 µg/dl, or it can be excluded in the upper half of the normal range [37]. In fact, cortisol concentrations greater than >19 µg/dl [38, 39] or 18 µg/dl [40, 41] virtually exclude AI. Values in the intermediate range require additional dynamic testing. Urinary free cortisol has only suboptimal sensitivity as normal values are observed in 20% of patients with AI [42]. Insulin tolerance test (ITT) (regular insulin 0.1 U/kg as iv bolus in normal weight and 0.15 U/kg in overweight subjects, with measurement of blood glucose and cortisol at 0, 30 and 60 min) is considered the gold standard for evaluation of the entire hypothalamo-pituitary-adrenal axis. Although several cut-offs for a normal cortisol response have been suggested [43], the traditional value of 18 µg/dl [38, 41, 44] allows a good separation between healthy individuals and patients with AI. It should be kept in mind, however, that not all normal subjects attain this level of response [45] and a normal cortisol rise may occur in patients with symptoms of AI [46]. For the test to be valid, glycaemia should fall below 40 mg/dl (2.22 mmol/l) and symptoms of hypoglycemia should develop. ITT is contraindicated in patients older than 60 years and in those with a history of seizures or with documented/suspected coronary artery disease. Metyrapone test (MT). When ITT is contraindicated, and where the compound is available (not in the U.S.A.) the metyrapone test (metyrapone 30 mg/kg body weight given with a snack at midnight with measurement of cortisol and 11-deoxycortisol at 8 AM of the following morning) may be performed. Metyrapone inhibits 11β-hydroxylase and, hence, the conversion of 11-deoxycortisol into cortisol, thereby reducing the negative feedback and triggering ACTH release which, in turn, increases 11-deoxycortisol
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production. Serum cortisol should decrease to less than 5 µg/dl, and 11-deoxycortisol should increase above 7 µg/dl. The sum of cortisol and 11-deoxycortisol after metyrapone should exceed 16.5 µg/dl [38, 47]. Both ITT and metyrapone may precipitate an acute adrenal crisis and should therefore be performed under close medical surveillance. High dose ACTH stimulation test (250 µg synthetic ACTH 1–24, cosyntropin, tetracosactin, Synacthen, as iv bolus with measurement of serum cortisol after 30, 60 min) directly assesses the adrenal secretory reserve, which may be impaired not only in primary AI but even in long-standing ACTH deficiency. Different cut-offs have been proposed and the most reliable appears to be cortisol peak greater than 18–20 µg/dl to exclude AI [48]. Recent onset or mild forms of secondary AI may not be detected by this test and a normal cortisol response does not exclude secondary AI [49], therefore ITT may be necessary to establish the diagnosis [50, 51]. Overall, peak cortisol levels at Synacthen and ITT testing appear in excellent agreement [52] and the high dose ACTH stimulation test may replace ITT in a substantial proportion of patients with suspected secondary AI. In minimally abnormal results the test should be repeated at least once, because the result is often normal on second assessment [53]. Low dose ACTH stimulation test (1 µg synthetic ACTH 1–24, Synacthen, as iv bolus with measurement of serum cortisol after 30, 60 min) has been proposed as a sensitive test for the diagnosis of secondary AI [54]. Using the cortisol >18 µg/dl criterion, this test allows an even better identification of patients with secondary AI compared with ITT [55–57] and the high dose ACTH test [58]. The advantage of the low dose compared with the high dose test may be offset by the technical difficulties inherent to dilution of 250 µg ampoules [59]. Due to the great difference in the 1–24 ACTH injected dose, a normal response with the high dose test is less reliable than with the low dose test whereas an insufficient response with the low dose test is less reliable than with the high dose test. In conclusion, since none of the above-mentioned tests correctly classify all patients, clinical judgment remains important. Differential diagnosis between primary and secondary AI Plasma ACTH concentration off glucocorticoid replacement therapy is the best parameter for the differential diagnosis, as levels are generally above 100 pg/ml in primary AI and low-normal in secondary AI. It is worth recalling that ACTH measurements are of little use in the initial diagnostic workup given the broad overlap between normal subjects and patients with central hypoadrenalism [60]. Prolonged ACTH infusion test (250 µg synthetic ACTH 1–24 injected into 500-ml bag of normal saline and infused
at a constant rate over 8 h and blood sampling for cortisol measurement performed at 6 and 8 h). This test was used to distinguish primary from secondary AI prior to the development of reliable ACTH assays. Theoretically, patients with primary AI may display a significant cortisol rise in response to an acute ACTH bolus but be unable to maintain sustained cortisol secretion. However, the sensitivity of this test in patients with hypothalamic-pituitary disease is not significantly greater than that of other ACTH tests [61]. CRH test (1 µg/kg ovine or human CRH as iv bolus with serial serum samples for cortisol measurement during the following 2 h) has been used to differentiate hypothalamic from pituitary disease in secondary AI. The lack of studies involving large numbers of patients and the high cost of CRH has greatly limited the use of this test. Diagnosis of IAD Once the diagnosis of secondary AI has been established, normal secretion of the other pituitary hormones, as well as the absence of structural pituitary defects, except for the typical changes in case of hypophysitis, have to be ascertained. ITT, GnRH and TRH tests can be used to fulfill the first requirement while MR of the hypotalamic-pituitary region is sufficient for the latter (Fig. 1). In patients with autoimmune endocrine disorders pituitary antibodies should be searched for, especially with imaging suspicious of hypophysitis. Genetic testing (see below) has so far proven to be of little use in adult IAD. Treatment Long-term replacement therapy Treatment requires replacement doses of glucocorticoids. For some patients with mild, near-to-asymptomatic disease, glucocorticoid replacement therapy may not be required except for stressful events. Administration of mineralocorticoids is generally not necessary as their production is maintained. Based on the present knowledge on cortisol production rate [62], the recommended glucocorticoid replacement dose for patients with AI is lower than in the past, and in particular for patients with secondary AI [41]: mean daily doses of 20 mg hydrocortisone (0.30 mg/Kg) or 25 mg cortisone acetate (0.35 mg/Kg) are usually sufficient, with two-thirds of the dose administered in the morning. Cortisone acetate is metabolized to cortisol by 11β-hydroxysteroid dehydrogenase and has a later onset of action and longer biologic half-life than hydrocortisone. Peak serum cortisol concentrations after steroid administration vary substantially among individuals but rapidly reach supraphysiological levels followed by a decline to initial levels 5–7 h after Springer
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Isolated ACTH Deficiency BIOCHEMICAL DIAGNOSIS
8 am serum cortisol < 3 µg/dl
3-18 µg/dl
highly suspicious for AI
suspicious for AI
>18 µg/dl
ITT, Synacthen Test 1 or 250 µg >18 µg/dl
Cortisol
