Download Isolated corticotrophin deficiency

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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Pituitary
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
Pituitary
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
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Pituitary
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 <18 µg/dl
AI
AI EXCLUDED
Normal
plasma ACTH
GH, TSH,
PRL,
high
low
LH & FSH
secretion
Primary
AI
AI:adrenal insufficiency
Secondary
AI
IAD: isolated ACTH deficiency
IAD
Normal
Pituitary imaging
Fig. 1 Proposed algorithm for the diagnosis of isolated ACTH deficiency
ingestion [63, 64]. This may result in low cortisol levels in
the late afternoon and impaired quality of life. Recent studies
indicate that thrice-daily regimens more closely mimics the
physiological steroid circadian profile [65, 66]. Long-acting
glucocorticoids can also be used in equivalent doses
(1 mg hydrocortisone = 1.25 mg cortisone acetate = 0.2 mg
prednisolone = 0.03 mg dexamethasone) but this may result
in unfavorably high nocturnal cortisol levels.
Reportedly, addition of dehydroepiandrosterone to glucocorticoid replacement therapy may exert positive effects on
well-being and mood in patients with adrenal insufficiency
[67]. However, treatment is hampered by the lack of pharmaceutically controlled preparations and large-scale studies are
needed. At the present time, dehydroepiandrosterone (50 mg
administered in the morning) should be reserved for patients
whose well-being is clearly impaired despite optimal glucocorticoid replacement.
Monitoring of glucocorticoid replacement therapy essentially relies on clinical judgment as no laboratory parameter
is fully reliable. Indeed, morning plasma ACTH as well as
cortisol levels are of little use and even urinary free cortisol
excretion [68] exhibits considerable interindividual variability [63], thus fine-tuning glucocorticoid therapy is often very
difficult. Urinary free cortisol levels may be of use to ex-
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clude underreplacement, e.g., non-adherence to therapy, or
overtreatment, i.e. iatrogenic Cushing’s syndrome.
Other therapeutic recommendations
In patients with non-isolated ACTH deficiency (partial or
total pituitary insufficiency), thyroid replacement therapy
should not be started before glucocorticoid replacement as
thyroid hormones accelerate cortisol metabolism and thus
may trigger an adrenal crisis if the patient has an inadequate
adrenal reserve.
Supervening stressful events, such as illnesses, trauma,
fever, major surgical or diagnostic procedures, mandate an
increase in glucocorticoid replacement dose (two to 10fold the maintenance dosage). Vomiting or diarrhea or other
causes of poor intestinal absorption call for intravenous hydrocortisone administration.
Patients on drugs that increase (e.g., phenytoin, rifampin, barbiturates) or decrease (e.g., protease inhibitors)
cytochrome P450 3A4 activity, a key enzyme for hepatic
glucocorticoid metabolism, may need higher or lower doses
of glucocorticoids [69, 70].
Pregnant women usually do not require adjustments in
their replacement dose although parenteral administration
Pituitary
may be needed to compensate for first trimester vomiting.
Labor and C-section should be approached as usual for stressful events.
Acute replacement therapy
Management of acute adrenal crisis requires immediate intravenous administration of 100 mg hydrocortisone, followed
by 100–200 mg over the next 24 h and large volumes of
saline under continuous cardiac monitoring.
Neonatal and childhood IAD
Neonatal or childhood IAD may have genetic causes. A defect in the ACTH precursor, proopiomelanocortin (POMC),
or in its cleavage enzyme, prohormone convertase, leads to
defects in POMC-derived peptides (e.g., ACTH, MSH) and,
hence, IAD; moreover, due to the dual role of α-MSH in
regulating food intake and hair pigmentation, the phenotype
associated with a defect in POMC should include obesity,
alteration in hair pigmentation and ACTH deficiency [71].
Other candidate genes are CRH and CRH receptor type 1,
but no mutations in these genes have been reported to be associated with IAD. Recently, mutations in TPIT, a pituitary
transcription factor crucial for correct corticotroph embryonic development, have been described in a considerable
proportion of neonatal IAD [72, 73].
Diagnosis
Hypoglycemia, seizures, prolonged jaundice and growth retardation are the prevalent symptoms in neonatal IAD [73]
and failure to establish a timely diagnosis may be fatal. Hydrocortisone should be administered immediately after obtaining blood samples for cortisol and ACTH. Identification
of TPIT mutations allows prenatal diagnosis for families
at risk and early glucocorticoid therapy in order to prevent
neonatal death [73]. Noninvasive prenatal diagnosis can also
be performed by measurement of estriol levels in plasma or
urine of a pregnant woman as decreased maternal estriol of
unexplained etiology may indicate fetal adrenal insufficiency
secondary to IAD [74].
In childhood, symptoms of adrenal insufficiency require
further investigation especially if associated with obesity and
red hair pigmentation.
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