Key words
idiopathic isolated adrenocorticotrophic hormone deficiency - pathogenesis - clinical features - diagnosis - treatment and prognosis
Introduction
Idiopathic isolated adrenocorticotrophic hormone (ACTH) deficiency (IIAD) is
characterized by the sole involvement of the pituitary-adrenal axis (HPA axis), low
serum cortisol levels, and low or normal ACTH levels, with no impairment or
transient reversible changes in the thyroid axis, gonad axis, prolactin axis, and
growth hormone axis function. Pituitary magnetic resonance imaging (MRI) is mostly
normal or displays empty sella syndrome. IIAD is divided into congenital IIAD
(CIIAD), which is thought to be genetic and heredity, whereas, in adult IIAD
(AIIAD), the etiology is unclear and often considered to be related to autoimmunity.
The clinical manifestations of IIAD are widespread and lack specificity, and many
patients remain undiagnosed for a long time. The aim of the study was to improve
clinicians' understanding of IIAD to improve the diagnosis rate.
Materials and Methods
Study subjects
The inclusion criteria for IIAD were as following: functional decrease in the HPA
axis only, serum cortisol levels below the normal range (AM:
185–624 nmol/L, PM:
<276 nmol/L), ACTH levels within the normal range (AM:
1.6–13.9 pmol/L, PM:
<1.6 pmol/L) or low (cortisol and ACTH levels were
measured by chemiluminescent immunoassay), normal levels of other anterior
pituitary hormones, and pituitary MRI is normal or shows empty sella. The
exclusion criteria for IIAD were as follows: abnormalities in other axes of the
anterior pituitary, history of glucocorticoid therapy, history of pituitary
surgery, and patients with tumors.
Clinical indicators
We collected the following patient information: gender, age at onset, length of
time from symptom onset to diagnosis, drinking history, first department visit,
clinical manifestations, routine blood tests (leukocytes, lymphocytes,
eosinophils, hemoglobin), blood glucose, electrolytes, the function of the HPA
axis, thyroid axis, gonad axis, and growth hormone axis; pituitary MRI, adrenal
gland computed tomography (CT), and type and dose of medication.
Statistical methods
Data were processed by SPSS 26.0. Normality testing of quantitative data was
performed by the Shapiro-Wilk test. Data that conformed to the normal
distribution were expressed as mean±standard deviation
(X±SD), non-normally distributed data were expressed
as median (interquartile range) (M [IQR]), and qualitative data were
expressed as percentages.
Ethics approval
This retrospective study involving human participants was in accordance with the
ethical standards of the institutional and national research committee and with
the 1964 Helsinki Declaration and its later amendments or comparable ethical
standards. The Medical Ethics Committee of Jining No.1 People’s Hospital
approved this study.
The study was not registered to a clinical trials registry (CTR)
The study was not registered to a CTR because it is a retrospective study.
Informed consent
In this retrospective study, ethics approval was obtained, and written informed
consent was not needed.
Results
General clinical characteristics
Sixteen patients were male and one was female. The minimum age at symptom onset
was 13 years and the maximum age was 80 years (median: 62 years). The length of
time from symptom onset to diagnosis ranged from 0 to 10 years (median: 2
months)([Table 1]), and were
mostly misdiagnosed as gastrointestinal diseases (6 cases), neurological or
psychiatric diseases (3 cases), and thyroid disease (1 case).
Table 1 Summary of the characteristics of 17 patients with
IIAD (n=17)
|
Indicators
|
IIAD (Frequency [Frequency], X±SD or
M [IQR])
|
|
Male, n (%)
|
16 (94.12%)
|
Female, n (%)
|
1 (5.88%)
|
Age at onset (years)
|
62 (20)
|
Length of time from symptom onset to diagnosis (months)
|
2 (29.8)
|
Drinking history, n (%)
|
2/16 (12.5%)
|
First department visited
|
|
4 (23.53%)
|
|
11 (64.71%)
|
|
2 (11.76%)
|
Gastrointestinal symptoms
|
|
15 (88.24%)
|
|
12 (70.59%)
|
|
8 (47.06%)
|
Neurological and psychiatric symptoms
|
|
7 (41.18%)
|
|
15 (88.24%)
|
Fatigue, n (%)
|
11 (64.71%)
|
Weight loss, n (%)
|
4 (23.53%)
|
Hypotension, n (%)
|
1 (5.88%)
|
Blood glucose
|
|
12 (70.59%)
|
|
3.5 (1.11)
|
Blood routine tests
|
|
3 (17.65%)
|
|
9 (52.94%)
|
|
0 (0%)
|
|
2 (11.76%)
|
Electrolytes
|
|
15 (88.24%)
|
|
11 (64.71%)
|
|
1 (5.88%)
|
|
0 (0%)
|
Function of the anterior pituitary
|
|
10.91 (33.33)
|
|
1.04 (2.95)
|
|
6 (35.29%)
|
|
1/13 (7.69%)
|
|
3 (17.65%)
|
|
0/2 (0%)
|
Pituitary MRI
|
|
10 (58.82%)
|
|
7 (41.18%)
|
Medication
|
|
17 (100%)
|
|
7.21±2.63
|
|
4 (23.53%)
|
IIAD idiopathic isolated adrenocorticotropic hormone deficiency,
X±SD mean±standard deviation, M (IQR) median
(interquartile range), ACTH adrenocorticotropic hormone, TSH thyroid
stimulating hormone, MRI magnetic resonance imaging.
Fourteen patients had both gastrointestinal and neurological or psychiatric
symptoms (82.35%). Among the 17 patients, the clinical manifestations
included anorexia (n=15, 88.24%), nausea (n=12,
70.59%), fatigue (n=11, 64.71%), vomiting (n=8,
47.06%), unconsciousness (n=7, 41.18%), and weight loss
(n=4, 23.53%) ([Fig.
1]). Furthermore, one patient had transient hypotension and there was
no decrease in blood pressure in three hypertensive patients. There were also
some rare manifestations, including loss of axillary and pubic hair (case
6).
Fig. 1 Percentage of clinical presentations.
Regarding the department that visited first, only four patients (23.53%)
were triaged to the endocrinology department for hypoglycemia or hyponatremia,
and among them, case 5 was first triaged to the endocrinology department because
of a history of hypothyroidism; 11 patients were triaged to the gastroenterology
department (64.71%); and two patients were triaged to the neurology or
psychiatry department (11.76%). Case 8, who had already been diagnosed
with IIAD 1 year prior, was triaged to the gastroenterology department again
when he showed gastrointestinal symptoms.
Five patients (cases 4, 7, 14, 15, 17) had a history of cerebral infarction and
case 1 had a history of cerebral hemorrhage. Three patients (cases 5, 10, 11)
were diagnosed with depression; their symptoms improved after changing to
cortisol therapy, so whether their depressive state was due to hyponatremia
cannot be excluded.
Laboratory tests
Fifteen patients had hyponatremia (88.24%), 11 patients had hypochloremia
(64.71%), one patient had hypokalemia, and none had hyperkalemia. The
median of blood glucose was 3.5 mmol/L, and 12 patients (70.59%)
had varying degrees of hypoglycemia (range: 1.1–3.7 mmol/L),
with three cases of hypoglycemic coma (case 2, 16, 17) and one of type 2
diabetes (case 1) who took metformin glibenclamide previously, his fasting blood
glucose was 3.17 mmol/L, which increased
(6.6–9.4 mmol/L) after supplementing with glucocorticoids.
Three patients had leukopenia, nine had anemia, two had eosinophilia, and none
had lymphocytosis.
Anterior pituitary function and imaging findings
HPA axis function was decreased in all 17 cases ([Table 2]). The median serum cortisol
and ACTH were 10.91 nmol/L and 1.04 pmol/L,
respectively. Thyroid antibodies were collected in 13 of the 17 patients. Seven
patients (41.18%) had thyroid disease, including elevated thyroid
stimulating hormone (TSH) in six patients (35.29%) and positive thyroid
autoantibodies in one patient (7.69%). Case 8 was previously diagnosed
with hypothyroidism due to Hashimoto's thyroiditis. Three patients
(17.65%) had hyperprolactinemia, but no occupancy was found on pituitary
MRI and no prolactinoma. Growth hormone levels were examined in two patients and
were found to be normal. Pituitary MRI was performed in 16 patients, and no
pituitary abnormality was seen in the remaining one patient by cranial CT; the
final results of imaging were empty sella in seven patients ([Fig. 2]) and normal in the remaining
10 patients. Adrenal CT examination found no abnormalities in seven
patients.
Fig. 2 Pituitary magnetic resonance imaging in seven patients with
empty sella (T2 image).
Table 2 Anterior pituitary functions and imaging findings
in 17 patients with IIAD (n=17)
Case number
|
gender
|
Age at onset (years)
|
COR nmol / L
|
ACTH pmol/L
|
TT3 nmol/L
|
TT4 nmol/L
|
FT3 pmol/L
|
FT4 pmol/L
|
TSH uIU/mL
|
Tg Ab IU/mL
|
TPOA b IU/mL
|
PRL ng/mL
|
FSH mIU/mL
|
LH mIU/mL
|
E2 pmol/L
|
P nmol/L
|
T nmol/L
|
GH ng/mL
|
Pituitary MRI
|
Adrenal gland CT
|
1
|
M
|
60
|
10.06
|
0.41
|
1.55
|
136.17
|
5.15
|
12.23
|
2.76
|
–
|
–
|
30.64
|
1.98
|
4.6
|
180
|
0.353
|
7.01
|
–
|
normal
|
normal
|
2
|
M
|
21
|
0.49
|
0.32
|
1.7
|
116.59
|
3.91
|
11.32
|
10.27
|
0
|
0.4
|
23.7
|
4.29
|
9.26
|
114.2
|
<0.159
|
24.73
|
0.07
|
empty sella
|
normal
|
3
|
M
|
53
|
10.91
|
<0.22
|
1.56
|
102.63
|
4.13
|
8.38
|
20.74
|
8.1
|
1.8
|
18
|
1.72
|
8.48
|
123.1
|
–
|
24.32
|
–
|
normal
|
–
|
4
|
M
|
63
|
75.91
|
5.65
|
0.64
|
126.26
|
2.79
|
15.83
|
2.223
|
0
|
15.7
|
11.46
|
3.34
|
2.6
|
115.9
|
–
|
17.23
|
–
|
normal
|
–
|
5
|
F
|
43
|
7.52
|
0.45
|
2.15
|
128.91
|
5.26
|
8.85
|
2.697
|
0.8
|
4.7
|
86.91
|
32.56
|
22.21
|
325.3
|
<0.159
|
<0.09
|
–
|
normal
|
–
|
6
|
M
|
62
|
7.31
|
<0.22
|
1.37
|
123.7
|
3.77
|
12.97
|
2.67
|
–
|
–
|
28.49
|
4.23
|
2.51
|
99.33
|
0.513
|
23.42
|
–
|
normal
|
–
|
7
|
M
|
76
|
9.61
|
0.28
|
1.46
|
130.54
|
4.42
|
8.77
|
5.12
|
1.9
|
13.8
|
53.09
|
8.74
|
12.36
|
200.8
|
0.266
|
33.14
|
–
|
empty sella
|
normal
|
8
|
M
|
61
|
26.56
|
2.6
|
–
|
–
|
2.53
|
0
|
52.18
|
>2464
|
213.3
|
22.65
|
9.93
|
8.82
|
97.36
|
–
|
21.13
|
–
|
empty sella
|
normal
|
9
|
M
|
62
|
18.7
|
4.69
|
1.85
|
144.43
|
5.5
|
19.22
|
2.67
|
0.2
|
0.2
|
17.68
|
4.02
|
4.95
|
165
|
<0.159
|
34.41
|
–
|
empty sella
|
normal
|
10
|
M
|
60
|
7.09
|
<0.22
|
1.52
|
97.83
|
4.23
|
12.83
|
6.37
|
0.6
|
0.9
|
18.76
|
7.75
|
5.94
|
211.2
|
–
|
27.08
|
–
|
normal
|
normal
|
11
|
M
|
13
|
98.24
|
3.68
|
0.95
|
105.92
|
3.9
|
15.88
|
8.76
|
0
|
0.3
|
34.84
|
8.53
|
9.02
|
31.04
|
0.344
|
12.13
|
–
|
normal
|
–
|
12
|
M
|
80
|
17.35
|
3.42
|
1.96
|
117.71
|
5.44
|
10.61
|
3.99
|
1.5
|
1.1
|
24.03
|
8.6
|
12.35
|
237.2
|
0.827
|
40.75
|
–
|
normal
|
–
|
13
|
M
|
64
|
54.49
|
3.08
|
–
|
–
|
3.98
|
10.72
|
3.61
|
42.9
|
1.4
|
61.5
|
10.23
|
17.47
|
–
|
–
|
18.12
|
2.06
|
normal
|
–
|
14
|
M
|
67
|
88.04
|
2.26
|
0.63
|
119.24
|
2.84
|
9.71
|
2.84
|
–
|
–
|
25.19
|
5.88
|
6.26
|
148.9
|
<0.159
|
19.44
|
–
|
empty sella
|
normal
|
15
|
M
|
72
|
1.61
|
0.65
|
1.57
|
150.52
|
5.19
|
18.78
|
2.88
|
0
|
0.2
|
28.05
|
5.04
|
11.59
|
225.4
|
–
|
39.24
|
–
|
normal
|
–
|
16
|
M
|
32
|
17.7
|
1.04
|
0.99
|
113
|
2.89
|
18
|
3.01
|
10.9
|
<9
|
10.6
|
2.22
|
3.77
|
144
|
<0.16
|
15.3
|
–
|
empty sella
|
–
|
17
|
M
|
68
|
3.25
|
<1.11
|
2.19
|
96.43
|
4.45
|
8.28
|
7.31
|
–
|
–
|
13.88
|
8.43
|
11.95
|
185.01
|
0.47
|
18.26
|
–
|
empty sella
|
–
|
M male, F female, COR cortisol (am:185–624,
pm: <276 nmol/ L), ACTH
adrenocorticotropic hormone (8:00–10:00 am, 1.6–13.9,
pm: <1.6 pmol/L), TT3 triiodothyronine
(1.25–2.73 nmol/L), TT4
tetraiodothyronine (69.97–152.52 nmol/L),
FT3 serum free triiodothyronine
(3.8–7 pmol/L), FT4 free thyroid hormone
(7.64–16.03 pmol/L), TSH, thyrotropin
(0.34–5.6 uIU/mL), TgAb thyroglobulin antibody
(0–4 IU/mL), TPOAb thyroid peroxidase antibody
(0–9 IU/mL), PRL prolactin (male:
4.0–15.2, female: 4.8–23.3 ng/mL);
FSH follicle stimulating hormone (male: 1.5–12.4,
female: post-menopausal 25.8–134.8 mIU/mL), LH
luteinizing hormone (male:1.7–8.6, female: post-menopausal
7.7–58.5 mIU/mL), E2 estradiol (male:
94.8–223, female: post-menopausal
<18.4–505 pmol/L), P progesterone
(male: 0.7–4.3, female: post-menopausal
0.3–2.5 nmol/L), T androgen (male:
9.9–27.8, female: 0.2–2.9 nmol/L),
GH growth hormone (male: 0.003–0.97, female:
0.01–3.61 ng/mL), - none.
Treatment and follow-up
No oral preparation of hydrocortisone was available in our center; therefore, all
patients were given prednisone tablets (mean dose: 7.21 mg/day)
after a clear diagnosis of IIAD. Although case 11 was a minor, his gonad axis
was initiating and his predicted outcome was satisfactory; thus, he was
administered prednisone tablets. At follow-up, the HPA axis function had not
recovered in all patients at the time of writing this article. Fig. 3 shows the
ACTH and cortisol levels of case 9 at multiple follow-ups.
Following prednisone supplementation, clinical symptoms and laboratory indicators
mostly returned to normal. Ten of 11 reviewed patients with hyponatremia had
returned to normal, although this was not so in case 8, which was considered to
be related to discontinuing prednisone tablets >10 days before
follow-up. All eight reviewed patients with hypoglycemia recovered, and two
reviewed patients with leukopenia were normal. Of the four reviewed patients
with anemia, two returned to normal and one reviewed case of eosinophilia
returned to normal. Of the three reviewed patients with elevated TSH, one (case
10) returned to normal, and one (case 11) showed a downward trend (8.76 to
6.59 µIU/mL).
Discussion
IIAD is a rare disease first proposed by Steinberg [1]. It is usually documented in case
reports or small case series in China [2]. The exact prevalence of IIAD is difficult to establish as there is no
consensus on the disease definition. In the past 9 years, 17 cases of IIAD were
reported at our center; the low incidence of this disease may be due to insidious
symptoms and lack of sufficient understanding of IIAD. This article provides a
comprehensive account of the whole process of diagnosis and treatment of IIAD cases
to improve physicians’ understanding of IIAD and increase the diagnosis
rate.
Potential pathogenesis of idiopathic isolated adrenocorticotrophic hormone
deficiency
The specific pathogenesis of IIAD is unknown; it may be related to genetic
defects, autoimmunity, pituitary ischemia, long-term alcohol consumption, drugs,
etc. ([Table 3]).
Proopiomelanocortin (POMC) is a precursor of ACTH, POMC deficiency syndrome is a
genetic defect disease, of which IIAD is one of the manifestations [3]. TBX19 encodes a transcription
factor specifically expressed in pituitary ACTH cells. Mutations in TBX19
eventually lead to ACTH deficiency [4], accounting for 65% of neonatal IIAD cases [5]. In our study, we observed an
adolescent patient (13 years old); unfortunately, neither he nor his parents had
undergone genetic screening. NFKB2 encodes a transcription factor that regulates
the expression of several immune-related genes, and mutations in NFKB2 may lead
to IIAD [6]. Prohormone convertase 1
(PC1) catalyzes the conversion of POMC proteins into ACTH; a structural mutation
in PC1 can ultimately lead to ACTH deficiency [7].
Table 3 Potential pathogenesis of IIAD
Potential pathogenesis of IIAD
|
Details
|
Genetic defects
|
|
Autoimmunity(highest probability)
|
-
IIAD is often associated with many autoimmune
diseases: Hashimoto's thyroiditis, primary
hypothyroidism, Graves' disease, type 1
diabetes, ulcerative colitis, Crohn's
disease, etc., especially autoimmune thyroid disease
[2]
[8];
|
|
|
|
|
|
|
|
|
Pituitary ischemia
|
-
Various vascular risk factors, such as hyperglycemia
and hypertension, can cause inadequate perfusion of
the pituitary, resulting in ischemic damage to the
pituitary [9]
[15].
|
Alcohol
|
|
Drugs
|
|
IIAD idiopathic isolated adrenocorticotropic hormone deficiency,
PC1 Prohormone convertase 1, ACTH adrenocorticotropic
hormone, ICI immune checkpoint inhibitor.
Autoimmunity is currently considered to be the most likely pathogenesis of IIAD
due to the following reasons. (1) IIAD is often observed in combination with
autoimmune diseases [8], such as
Hashimoto's thyroiditis, primary hypothyroidism, type 1 diabetes,
Crohn's disease, etc. [2].
Thyroid disease may be due to the similarity between certain antigens in ACTH
cells and thyroid follicular epithelial cells [9]. (2) Pituitary tissue from IIAD
patients exhibits infiltration of lymphocytes [10]. Fujita's study confirmed
the presence of anti-ACTH antibodies in 58% of IIAD patients [11]. (3) Patients with traumatic brain
injury were also diagnosed with IIAD due to immune system attacks on exposed
ACTH cells [12]. (4) Immune
checkpoint inhibitors (ICIs) cause IIAD in 0.8% of patients [13], because over-activated immune
cells lead to autoimmune damage. (5) The formation of the empty sella may be
related to autoimmunity [14]. Seven
patients in our center showed an empty sella, providing much evidence to suggest
that autoimmunity is involved in the pathogenesis of IIAD.
Some vascular high-risk factors or pituitary ischemic diseases, such as type 2
diabetes, hypertension [15], cerebral
hemorrhage [9], cerebral infarction,
etc., may lead to inadequate pituitary perfusion and cause IIAD. Our center has
one patient with type 2 diabetes, three hypertensive patients, one cerebral
hemorrhage patient five cerebral infarction patients. Furthermore, studies have
reported that a history of chronic alcoholism may be associated with the
development of IIAD [16]
[17]. Chronic alcohol intoxication can
cause ultra-microscopic pathological changes in the endocrine cells of the rat
adenohypophysis, resulting in pituitary damage [18]. In our study, two patients had a
long-term history of alcohol consumption; however, the the relationship between
alcoholism and IIAD remains unknown. Long-term history of the use of opioid
drugs can inhibit endogenous endorphin production and the generation of ACTH
[19]
[20].
The pathogenesis of IIAD has not yet been fully defined. It is a complex
condition involving multiple factors, and further clinical studies are needed to
summarize and confirm these factors. Of course, IIAD may be a heterogeneous
group of conditions; future developments will allow us to better subclassify
different types of IIAD, and at that point, we will develop a more fitting name
for this condition.
Clinical characteristics of idiopathic isolated adrenocorticotrophic hormone
deficiency
The clinical manifestations of IIAD are diverse and lack specificity. As a
result, patients with IIAD may often first visit the department of
gastroenterology and not the endocrinology department. Many patients remain
undiagnosed for a long time. The population with IIAD is predominantly
middle-aged and elderly, and predominantly male. One study involving 72
patients, reported the male-to-female ratio as 1.2:1, and although the disease
was distributed in all age groups, it was predominant in the 50–60 years
age group [16]. Our study included 16
male and only one female, and the median age was 62 years; the clinical
manifestations usually started with gastrointestinal symptoms or neurological
symptoms, manifesting as anorexia, nausea, fatigue, vomiting, unconsciousness,
and weight loss. Likewise, the major clinical manifestations of
Iglesias’s study were fatigue, anorexia, nausea or vomiting [21]. Patients with CIIAD usually have
severe hypoglycemia, seizures, and prolonged cholestatic jaundice [22]. The clinical manifestations of
the patients in our study were generally consistent with those reported in
previous studies in China and foreign countries [8]
[23]. Laboratory tests in our study
mostly showed hyponatremia (88.24%) and hypoglycemia (70.59%),
with hyponatremia also being the most common laboratory finding in the studies
by Iglesias (68.2%) [21] and
Hannon (39.13%) [8]. In one
study, eosinophilia (31.8%) was common in IIAD caused by ICIs [21], while our study only had two
patients with eosinophilia (11.76%); this discrepancy is considered to
be related to ICI because eosinophils are involved in immunity.
In Japan, approximately 10% of the more than 300 IIAD cases were found to
be complicated with thyroid disease, with Hashimoto's thyroiditis being
the most common [24].
Murakami’s study speculated that elevated TSH is mostly related to
cortisol deficiency rather than autoimmunity [25]. However, data derived from the
National Pituitary Database of Ireland showed that 12 (56.52%) of 23
patients had autoimmune disease, including nine patients (39.13%) with
documented autoimmune hypothyroidism, highlighting an autoimmune basis for
patients with autoimmune hypothyroidism and IIAD [8]. Two patients with high prolactin
levels were reported in the study by Sun Chan, which returned to normal after
supplementing with glucocorticoids. The high prolactin levels may be related to
cortisol deficiency because prolactin was found to overreact in patients with
IIAD in response to thyrotropin-releasing hormone, which resumed to normal level
after glucocorticoid replacement [26]. There were three hyperprolactinemia cases in our study, and
pituitary MRI excluded prolactinoma. Unfortunately, the lack of follow-up
information restricts our ability to know whether the prolactin levels of these
patients decreased after glucocorticoid supplementation.
Diagnosis of idiopathic isolated adrenocorticotrophic hormone
deficiency
The key to diagnosing IIAD is evaluating anterior pituitary function ([Fig. 4]). The diagnosis of IIAD
includes the following elements: the fasting serum cortisol at 8 am without
stress of <80 nmol/L (3 µg/dL)
(>500 nmol/L [18 µg/dL] can be
excluded) [27], the ACTH levels
should be either low or normal, and other anterior pituitary hormones levels are
normal. If available, ACTH excitation tests can be performed to confirm that the
hypoadrenocorticism in the patient is secondary (in patients with longer disease
duration, ACTH stimulation tests may give false negative results). In addition,
pituitary MRI shows it to be mostly normal or empty sella, and the adrenal gland
can be shriveled due to a prolonged lack of ACTH [28]. Hematological examination mostly
shows hyponatremia and hypoglycemia, and if available, anti-pituitary antibody
testing should be implemented to assess the involvement of immune factors.
Furthermore, genetic screening should be performed when a newborn is suspected
to have IIAD.
Fig. 3 Folding graph of cortisol and ACTH levels in case 9.
Fig. 4 Diagnostic process of IIAD.
Differential diagnosis of idiopathic isolated adrenocorticotrophic hormone
deficiency
Being familiar with the differential diagnosis of IIAD helps to improve the
diagnosis rate. For example, compared with primary adrenocortical hypofunction,
patients with IIAD do not have skin pigmentation and a reduction in cortisol and
ACTH. In addition, the non-specific symptoms of patients with IIAD are often
similar to those of gastrointestinal disease, cardiovascular disease, and
neurological or psychiatric disease; however, the symptoms of gastrointestinal
disease are regular, whereas IIAD patients lack regular symptoms and symptomatic
treatment is invalid. Hypotensive shock and coma associated with cardiovascular
disease mostly occur with underlying vascular diseases, while coma and seizures
in patients with IIAD are mostly due to hypoglycemia and hyponatremia. These
symptoms are recovered quickly after supplementing IIAD patients with
glucocorticoids.
Treatment and prognosis of idiopathic isolated adrenocorticotrophic hormone
deficiency
The treatment of IIAD broadly follows the treatment principles of secondary
adrenocortical hypofunction [29].
Glucocorticoid supplementation is the first choice, and the main oral drugs are
hydrocortisone and prednisone, and hydrocortisone is generally preferred [13]. The doses of hydrocortisone are
as follows: 10–25 mg/day for adults and 8–10
[mg/m2]/day for children. The mode of administration is mostly
half to two-thirds of the total dose at 8 am, followed by the remaining dose
given divided and given once or twice at noon and/or in the evening.
Adult patients can be administered prednisone [30]. The dose is
3–7.5 mg at 8 am alone. The selection of drug dose should be
individualized; mild patients do not require interventions during non-stressful
conditions, but glucocorticoid supplementation is required during stressful
conditions. In other patients, the dose should be adjusted upward during
stressful conditions, such as fever, surgery, and adrenal crisis. Whether the
supplement dose is appropriate is mainly based on clinical manifestations and
laboratory tests rather than cortisol and ACTH levels. Prenatal diagnosis is
recommended for pregnant women with a family history of IIAD, and tumor patients
treated with ICIs require monitoring of the HPA axis function both during
treatment and following treatment completion because the effects of ICIs persist
even after discontinuation [31]
[32].
The symptoms and laboratory indicators of IIAD mostly return to normal after
glucocorticoid supplementation; however, the HPA axis function had not recovered
in all patients at the time of writing this article. In another study, some
patients progressed to hypofunctioning of multiple pituitary axes [8]; strictly speaking, these patients
cannot be diagnosed with IIAD and be more appropriately diagnosed with partial
or total hypopituitarism.
Conclusions
In conclusion, IIAD has an insidious onset and atypical symptoms and can seriously
affect the quality of life. The possibility of IIAD should be considered in any
patient with acute, unexplained recurrent anorexia, fatigue, hyponatremia, or
hypoglycemia. In addition, for patients with hypertension or diabetes, we should be
alert to the possibility of IIAD when a sudden drop or significant improvement in
blood pressure or blood glucose occurs or even with the appearance of
non-drug-related hypotension or hypoglycemia [15]. Finally, more cases are required to understand the clinical
characteristics of IIAD, thus further improving the diagnosis rate.
The limitations of this study are as follows: (1) the study focused on a rare
disease; thus, the sample size was small, (2) due to limited laboratory conditions
and the physical condition of the patients, the study failed to complete ACTH
provocation test and insulin stress test, and (3) no pathological evidence was
available.
Ethics Approval and Informed Consent
This retrospective study involving human participants was in accordance with the
ethical standards of the institutional and national research committee and with the
1964 Helsinki Declaration and its later amendments or comparable ethical standards.
The Medical Ethics Committee of Jinjing No.1 People’s Hospital approved this
study. In this retrospective study, ethics approval was obtained, and the written
informed consent was not needed.