Journal of the Endocrine Society, 2022, 6, 1–7
https://doi.org/10.1210/jendso/bvac119
Advance access publication 04 August 2022
Clinical Research Article

Frequency of Adrenal Insufficiency in Patients
With Hypoglycemia in an Emergency Department:
A Cross-sectional Study
Tetsuya Kawahara,1,

Maiko Tsuji,2 Naoki Tominaga,2 Nagahiro Toyama,2 and Mikio Toda3

Department of Endocrinology and Diabetes, Shinkomonji Hospital, Kitakyushu, Japan
Department of Emergency Medicine, Shinkomonji Hospital, Kitakyushu, Japan; and3
Department of Internal Medicine, Shinkomonji Hospital, Kitakyushu, Japan
1

Correspondence: Tetsuya Kawahara, MD, PhD, Department of Endocrinology and Diabetes, Shinkomonji Hospital, 2-5 Dairishinmachi, Moji, 8000057
Kitakyushu, Japan. Email: k-tetsuy@med.uoeh-u.ac.jp

Abstract
Context: In most patients presenting with hypoglycemia in emergency departments, the etiology of hypoglycemia is identified. However, itcannot be determined in approximately 10% of cases.
Objective: We aimed to identify the causes of unknown hypoglycemia, especially adrenal insufficiency.
Methods: In this cross-sectional study, we evaluated the etiology of hypoglycemia among patients in our emergency department with hypoglycemia (plasma glucose level < 70 mg/dL (3.9 mmol/L)] between April 1, 2016 and March 31, 2021 using a rapid adrenocorticotropic hormone(ACTH) test.
Results: There were 528 cases with hypoglycemia included [52.1% male; median age 62 years (range 19-92)]. The majority [389 (73.7%)] ofpatients were using antidiabetes drugs. Additionally, 33 (6.3%) consumed alcohol; 17 (3.2%) had malnutrition; 13 (2.5%), liver dysfunction; 12(2.3%), severe infectious disease; 11 (2.1%), malignancy; 9 (1.7%), heart failure; 4 (0.8%), insulin autoimmune syndrome; 3 (0.6%), insulinoma;
2 (0.4%) were using hypoglycemia-relevant drugs; and 1 (0.2%) suffered from non-islet cell tumor. Rapid ACTH tests revealed adrenal insufficiency in 32 (6.1%). In those patients, serum sodium levels were lower (132 vs 139 mEq/L, P < 0.01), eosinophil counts were higher (14 vs 8%,
P < 0.01), and systolic blood pressure was lower (120 vs 128 mmHg, P < 0.05) at baseline than in patients with the other etiologies.
Conclusion: The frequency of adrenal insufficiency as a cause of hypoglycemia was much higher than what we anticipated. When protracted
hypoglycemia of unknown etiology is recognized, we recommend that the patient is checked for adrenal function using a rapid ACTH test.
Key Words: adrenal insufficiency, hypoglycemia, rapid ACTH test, emergency department

If one considers all patients with altered mentation presenting in the emergency department, hypoglycemia has
been identified as the underlying process in approximately
7% of cases [1]. While the most common causes of hypoglycemia are antidiabetes drugs, there are many other causesof hypoglycemia, and in approximately 10% of cases, theetiology of hypoglycemia cannot be determined [2, 3], andglucose infusion is routinely used to maintain patients’ blood
glucose levels.
Adrenal insufficiency (AI) is 1 cause of hypoglycemia. AI isthe lack of cortisol (glucocorticoid) and/or aldosterone (mineralocorticoid) secretions from adrenal glands. AI is classified
as primary (Addison disease), caused by diseases of the adrenal
cortex; secondary, caused by impaired adrenocorticotropic
hormone (ACTH) secretion due to pituitary abnormalities;
and tertiary, caused by insufficient corticotropin-releasing
hormone (CRH) secretion and function because of hypothalamic dysfunction [4-6]. The prevalence of primary AI is estimated at between 82 and 144 cases per million population inWestern societies [7, 8] compared to an estimated 138 to 142
cases per million population in Japan [9, 10]. The currently

estimated incidences of this disorder are 4.4 to 6.0 and 6.6
new cases per million population per year in Western societies[11] and in Japan [9], respectively, and it presents most often
between 30 and 50 years of age [10, 12, 13]. Secondary AI occurs more frequently than primary AI [10, 14]. Its estimatedprevalence is 150 to 280 per million [15, 16], and affectedpatients are often diagnosed in their 60s [10, 17]. The mostcommon cause of tertiary AI is chronic exogenous administration of synthetic glucocorticoids, which causes prolonged
suppression of hypothalamic CRH secretion through negative
feedback mechanisms [18, 19]. Patients with chronic AI may
develop acute AI (adrenal crisis) under stress such as infection, surgery, etc. Adrenal crisis is a fatal condition that causes
circulatory disorders due to an absolute or relative deficiencyof glucocorticoids. The estimated incidence is 6 to 8 and 6.3
per 100 chronic AI patients per year in Western societies andJapan, respectively [10, 16]. Therefore, detecting AI is criticalin emergency medical care.
The objective of this study was to identify the cause of
hypoglycemia of unknown etiology, especially AI, in emergency departments.

Received: 14 June 2022. Editorial Decision: 31 July 2022. Corrected and Typeset: 27 August 2022
© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided theoriginal work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

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2

2

Methods
Study Population
This was a 5-year single-center cross-sectional study to investigate the causes of unexplained hypoglycemia. Inclusion
criteria were male and female patients aged ≥18 years withhypoglycemia [plasma glucose level < 70 mg/dL (3.9 mmol/L)]
with or without hypoglycemic symptoms who presented tothe emergency department between April 1, 2016 and March
31, 2021. Furthermore, rapid ACTH test was performed on

Journal of the Endocrine Society, 2022, Vol. 6, No. 10

all patients who met inclusion/exclusion criteria except those
whose cause of hypoglycemia was found to be antidiabetes
drugs. Exclusion criteria were patients whose plasma glucose
level was ≥70 mg/dL with hypoglycemic symptoms, patients
who refused a rapid ACTH test, and patients who were pregnant. Also excluded were patients who have participated inother clinical trials, and patients who were judged by their
physician to be ineligible for participation. This trial was approved by the institutional review board at Shin Komonji

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Figure 1. Study flow diagram.

Journal of the Endocrine Society, 2022, Vol. 6, No. 10—
1 (0.2)
Data are given as n (%).
Abbreviation: AI, adrenal insufficiency.
aPercentage of the total 528 patients.
b
Percentage of concomitant AI of each etiology.

Without AI

389 (73.7)

33 (6.3)

17 (3.2)

13 (2.5)

12 (2.3)

11 (2.1)

9 (1.7)4 (0.8)3 (0.6)2 (0.4)2 (0.4)32 (6.1)
1 (0.2)0 (0)2 (0.4)

0 (0)
0 (0)

2 (0.4)3 (0.6)

0 (0)
0 (0)

4 (0.8)9 (1.7)0 (0)4 (26.7)

15 (2.8)
19 (3.6)

7 (36.8)0 (0)13 (2.5)389 (73.7)
Subjectsa

1 (5.6)

Liverdysfunction
Malformation
Alcoholabuse
Antidiabetes
drugs
Etiologies

Table 1. Etiologies of hypoglycemia

Among the total of 17 821 patients who presented to ouremergency department during the 5-year observation period,
528 patients were included in the study (Fig. 1). Of the 528
patients, 507 (96.0%) presented hypoglycemic symptoms,
such as tremor, palpitations, sweating, hunger, paresthesia,dizziness, weakness, and confusion. Median age was 62 years(range 19-92), 52.1% were men, and mean plasma glucose
levels were 48.5 mg/dL (95% CI 31.5-54.7 ng/dL) at the
emergency department. Etiologies of hypoglycemia included
389 (73.7%) patients using antidiabetes drugs; 35 (6.6%)
consumed alcohol; 19 (3.6%) had severe infections and/or
sepsis; 18 (3.4%), malabsorption and/or undernutrition; 15(2.8%), malignancies; 13 (2.5%), liver dysfunction; 9 (1.7%),
heart failure; and 2 (0.4%) using hypoglycemia-relevant
drugs. These were disopyramide phosphate and angiotensinconverting enzyme inhibitor. No checkpoint inhibitor wasused. In addition, we found that 4 (0.8%) had insulin autoantibody syndrome, 3 (0.6%) had insulinoma, and 1 (0.2%)
had non-islet cell tumor. The cause was unknown in 2 patients (0.4%), who were patients undergoing hemodialysis
without diabetes (Table 1; Fig. 2).
One hundred thirty-nine patients whose etiology could
not be diagnosed in the emergency department or who did
not take any antidiabetes drugs underwent rapid ACTH
tests as the previously noted etiologies may not be the actual
cause of hypoglycemia. Testing revealed AI in 32 (6.1%) of

Severeinfection

Characteristics of Study Subjects

18 (3.4)

Results

2 (5.7)

Malignancy

HeartfailureAnalysis of variance and Dunnett’s test were performed
to compare the AI-induced hypoglycemia group as a control group with other hypoglycemia groups. Statistical analyses were conducted using R-software, version 4.05 (RFoundation for Statistical Computing, Vienna, Austria). Twosided P-values < 0.05 were considered statistically significant.

35 (6.6)

Statistical Analyses—

Insulinautoimmune

The primary outcome was the rate of AI in patients withhypoglycemia presented to our emergency department. In
addition, we investigated the clinical manifestations in eachhypoglycemic etiology group.

Cooccurrenceof AIbhypoglycemiarelated drugs
Insulinoma

Outcome Measures

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The cause of hypoglycemia was investigated in those patients who qualified for the study. In the emergency department, a rapid ACTH loading test (250 µg synthetic 1-24
ACTH: tetracosactide acetate administered intravenously)
was performed on all patients except those who were taking
antidiabetes drugs. Blood specimens were collected bynurses before loading and at 30 and 60 minutes after ACTH
administration.
The diagnostic criterion for AI was peak serum cortisol
levels of <18 μg/dL post rapid ACTH test [10, 20, 21]. Insulin
tolerance test, CRH loading test, and/or continuous ACTH
loading test were performed on patients who were diagnosed
with AI to identify primary (adrenal), secondary (pituitary),or tertiary (hypothalamic) AI (Fig. 1).

Non-islet
cell tumor

Procedures

Unknown

Adrenalinsufficiency

Hospital. Written informed consent was obtained from allparticipants before enrollment in the trial.

14 (43.8)

3

Journal of the Endocrine Society, 2022, Vol. 6, No. 10

4

Table 2. Differences between non-AI and AI regarding the response to rapid ACTH test

AI (n = 32)
Serum cortisol levels, µg/dL(reference range 4.5-21.1)

Non-AI(n = 107)

Primary(n = 3)

Secondary (n = 27)

Tertiary (n = 2)

P-values

Baseline

8.5 ± 1.3

4.3 ± 2.0

4.5 ± 1.5

3.9 ± 1.3

0.035*

After 30 minutes

19.7 ± 4.1

8.1 ± 3.6

7.3 ± 2.3

5.6 ± 2.8

0.007**

After 60 minutes

23.9 ± 5.7

9.2 ± 4.0

9.8 ± 3.4

8.1 ± 3.5

0.004**

Data are given as mean ± SD.
Abbreviation: AI, adrenal insufficiency.
*
P < 0.05.
**
P < 0.01.

528 patients. The differences between the non-AI and AI regarding the response to rapid ACTH test is shown in Table
2. Subsequent tests revealed the following: 3 were primary,
27 were secondary (pituitary), and 2 were tertiary (hypothalamic) (Fig. 1). Of the 3 patients with primary AI, 1 had
21-hydeoxylase deficiency, 1 suffered from a fungal infection, and 1 had a bilateral adrenal metastasis of lung cancer.
Of the 27 patients with secondary AI, all had an isolated
ACTH deficiency. Both patients with tertiary AI were chronic
steroid users.
AI was found in 2 (5.7%) of the 35 patients with alcoholabuse, 7 (36.8%) of the 19 with severe infection and/or sepsis,
1 (5.6%) of the 18 with malnutrition, and 4 (26.7%) of the
15 with malignancies (Table 1). Of the 4 patients with malignancies and AI, 1 had a bilateral metastasis of lung cancer
who suffered from a primary AI. The others had neither metastasis nor adrenal cancer, but 2 had breast cancer and 1 hadcolorectal cancer, and they suffered from secondary AI.
In comparing hypoglycemic patients induced by AI withthose induced by other etiologies, the former had significantly
lower serum potassium levels (132 vs 140 mEq/L, P = 0.007),
lower systolic blood pressure (120 vs 128 mmHg, P = 0.039),

and higher eosinophil counts (14 vs 8%, P = 0.002). There
were no significant differences in blood glucose levels(P = 0.31) (Table 3).

Discussion
In our study, AI was found to be the third-highest etiology[32/528 (6.1%)] after antidiabetes drugs [389/528 (73.7%)]
and alcohol abuse [35/528 (6.6%)], among the hypoglycemic
patients transported to the emergency department. Previous
reports showed that the etiologies of hypoglycemia transported to emergency departments were antidiabetes drugs in
54% to 88% [1], unrelated to diabetes in 12% to 46% [22],and unknown in 1% to 6% [2, 3].
The primary causes of hypoglycemia are insulin and oral
hypoglycemic drugs. Patients with type 1 diabetes who usedinsulin had 1 to 3.2 hypoglycemic attacks per year [23, 24],and type 2 diabetic patients with ≥5 years of insulin treatment experienced an average of 0.7 hypoglycemic attacks per
year [24]. Patients prescribed oral hypoglycemic drugs, especially sulfonylureas, were also at high risk of hypoglycemia[25]. The incidence of hypoglycemia in patients with type 2

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Figure 2. Percentage of each etiology in patients with hypoglycemia. Out of 528 patients with hypoglycemia transported to our emergency
department, 389 (73.7%) were on antidiabetes drugs; 35 (6.6%) had alcohol abuse problem; 32 (6.1%), adrenal insufficiency; 18 (3.4%), malnutrition;
15 (2.8%), liver dysfunction; 11 (2.1%), malignancy; 9 (1.7%), heart failure; 7 (1.3%), severe infection; 4 (0.8%), insulin antibody syndrome; 3 (0.6%),
insulinoma; 2 (0.4%) were receiving hypoglycemia-related drugs; 2 (0.4%) had unknown etiology; and 1 (0.2%), non-islet cell tumor.

nsAbbreviations: BMI, body mass index; systolic BP, systolic blood pressure; CRP, C-reactive protein; na, not significant; serum K, serum kalium; serum Na, serum natrium.
*P < 0.05.
**
P < 0.01.

ns

8.13

2.06

3.8

2.37
1.03
0.75

3.6
4.1

1.12
1.70

3.9
3.5

3.25
18.6

3.8
4.1

1.12
0.72

3.4

0.58
CRP, mg/dL

3.0
4Serum K, mEq/L

0.84

3.7

5.6

3.9

ns

0.007**
136

132

178

141

138

243

139
140

221
219

141
139

178
206

147
140

223

137
143
Serum Na, mEq/L

166
211
Total cholesterol, mg/dL 239

135

207

175

184

ns

0.002**
9

14

28

7
6
8

42
31

11
6

35
27

5
8

40
31
32

10
8
4
Eosinocyte, %40
36
Lymphocyte, %

5

39

46

39

ns

ns
8500
4600
5200
White blood cells, μL

3900

4100

12800

4800

6200

3500

4800

6700

5100

3900

ns

11.6
13.7
14.6
Hemoglobin, mg/dL

11.9

13.4

13.7

11.6

12.9

14.7

15.9

13.8

13.5

12.4

0.039*

50

48

129

45
62
50

132
134

46
59

125
128

53
51

129
134
128

52
51
47
Plasma glucose, mg/dL

129
137
Systolic BP, mmHg

56

130

128

120

ns

ns
20.5
23.6
BMI kg/m2

19.8

22.7

21.7

18.2

20.7

22.5

27.1

24.6

19.7

21.5

ns

21.3

52

63

100
50
71
49
Male, %

60

50

54

56

50

50

67

50

68
71

32 (6.1)
1 (0.2)2 (0.4)69
58

3 (0.6)4 (0.8)65
70

9 (1.7)
11 (2.1)

68
71

12 (2.3)
13 (2.5)
17 (3.2)

59
65
61
Age, years

33 (6.3)
389 (73.7)
Subjects, n (%)

67

2 (0.4)

Non-islet
cell tumor
hypoglycemiarelated drugs
Insulinoma
Insulinautoimmune
HeartfailureMalignancy
Severeinfection
Liverdysfunction
Malformation
Alcoholabuse
Antidiabetes
drugs

diabetes treated with oral hypoglycemic drugs was reportedly
0.35× per year [26].
Alcohol inhibits gluconeogenesis in the body but does notaffect glycogenolysis [27]. Thus, hypoglycemia occurs after
several days of alcohol consumption with limited ingestionof food and after hepatic glycogen stores are depleted [28].
Alcohol ingestion is often the cause of, or a contributing
factor to, hypoglycemia encountered in patients coming toemergency departments.
In our study, we found that the ratio of secondary and tertiary AIs, rather than primary AI, was as high as 29/32 (90.1%)
in all types of AI. It is rare for adult primary AI to cause
hypoglycemia in the absence of infection, fever, or alcohol ingestion [29]. In contrast, hypoglycemia is more common insecondary AI caused by isolated ACTH deficiency [30-32]. As
a result, we concluded that Addison’s disease would be diagnosed quickly and treated; however, ACTH insufficiency wasoften overlooked, possibly because the absence of dehydration and hypotension permits patients to tolerate their illness
longer. In accordance with the guidelines [10, 21, 33], administration of hydrocortisone to our AI patients promptly improved their hypoglycemia, and glucose administration was
no longer necessary. It is beneficial to make an early diagnosis
of AI because it is not necessary to continue to administer
glucose wastefully. In addition, in septic shock, patients withAI showed the depressed pressor sensitivity to noradrenaline,
which may be substantially improved by physiological dosesof hydrocortisone [34]. Eventually, of the 32 patients with AI,
21 (65.6%) improved their hypothalamic-pituitary-adrenal
axis and no longer needed hydrocortisone to maintain theirblood glucose.
In addition to hypoglycemia, clinical manifestations of
AI included hyponatremia (serum natrium < 135 mEq/L),
normocytic normochromic anemia (male, <13 g/dL; female,<12 g/dL), low serum total cholesterol level (<150 mg/dL),
eosinophilia (>8%), relative leukopenia, hypotension, andhyperkalemia (serum potassium > 4.5 mEq/L) [10, 21, 35].
However, in our study, 3 symptoms—hyponatremia, hypotension, and eosinophilia—were more frequently observed in AI
as compared to other etiologies of hypoglycemia.
Hyponatremia can occur in both primary and secondary
AIs and is found in 70% to 80% of patients with AI [35].
The underlying etiology is different in each case. In primaryAI, hyponatremia and hypovolemia are caused by aldosterone
deficiency, whereas in secondary AI, hyponatremia is due tothe lack of cortisol, which leads to increased vasopressin secretion and dilutional or hypervolemic hyponatremia [19, 35,36]. Hyponatremia can occur early in the disease and maybe
the initial manifestation [37]; in contrast, the number of patients with hyperkalemia was not significantly large in ourstudy. Hyperkalemia often occurs due to aldosterone deficiency. Therefore, hyperkalemia is observed in patients withprimary AI who have both aldosterone and cortisol secretory
deficiency. In contrast, patients with secondary or tertiary
AI usually have normal mineralocorticoid function due tocompensation for the intact renin-angiotensin system. In ourstudy, hyperkalemia did not occur in the AI group because theproportion of secondary and tertiary AI was overwhelmingly
higher than that of primary.
Heart rate and systolic blood pressure in hypoglycemia
without AI are slightly raised. In secondary and tertiary AI,
hypotension is less prominent [6, 30]. However, in most patients with primary AI, the blood pressure is low, and some

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Table 3. Clinical manifestation of hypoglycemia

5

Unknown

Adrenalinsufficiency

P-values

Journal of the Endocrine Society, 2022, Vol. 6, No. 10

6Funding
This study was supported by a grant from the Kitakyushu
Medical Association. The sponsor did not contribute to thedesign, collection, management, analysis, interpretation ofdata, writing of the manuscript, or the decision to submit themanuscript for publication.

Disclosures
The authors have nothing to disclose.

Author Contributions
T.K. wrote the first draft of the manuscript and was mainly
responsible for the designation of the methodology. All authors were responsible for the critical revision of the article for important intellectual content. T.K., M.T., N.T., andT.N. were responsible for the collection and assembly of
data. M.T. was responsible for data management. T.K. completed the main part of the data analyses, and all authors
discussed the analysis plan and results and provided input
to the manuscript. All authors had access to the final study
results and were responsible for the final approval of themanuscript.

Data Availability
The data that support the findings of this study are not publicly available because they were used under license for thecurrent study only. However, the corresponding author willon request detail the restrictions and any conditions underwhich access to some data may be provided.

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have postural hypotension. These symptoms are primarily
due to volume depletion resulting from aldosterone deficiency[38]. Glucocorticoids are necessary for adrenal medullaryepinephrine synthesis, and patients with AI have decreased
serum epinephrine and a compensatory increase in serum
norepinephrine concentrations [39]. This may cause slightly
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Relative eosinophilia was reported to be a marker of AI[10, 40]. One study found that the combination of a historyof glucocorticoid withdrawal, nausea, hyperkalemia, and eosinophilia was a useful predictor of AI in an inpatient population [41]. In contrast, subsequent small series suggested thatthe eosinophil count is >500/µL in <20% of patients with AI[42]. Therefore, the presence of eosinophilia was found incidentally; other causes such as allergy or infection should also
be investigated [43].
In our study, there were 2 patients with hypoglycemia
whose etiology was undetermined; however, both were undergoing hemodialysis. Chronic kidney disease likely involves
impaired gluconeogenesis, reduced renal clearance of insulin,
and reduced renal glucose production [44], which may increase the risk of hypoglycemia. However, previous dataon chronic kidney disease as a risk factor for hypoglycemia
has been conflicting. Some [45, 46] but not all [47] previous
studies have noted such an association.
This was a single-center prospective observational study
where the results were obtained at a facility with an endocrinology and emergency medicine specialist in the Kitakyushu
area of Japan. Thus, the generalizability of the proportion of
hypoglycemic patients and the proportion of patients withdiabetes among all patients in emergency departments is unknown. An ACTH test may not be available in all facilities
and the turnaround time on the test if available may preclude
this diagnosis being made in the emergency department. In
addition, because the rapid ACTH test was not performed in
the emergency department on the hypoglycemic patients who
used antidiabetes drugs due to the study protocol, the proportion of AI may have been higher if testing had been performed
for all patients. However, after admission, rapid ACTH tests
were performed on the 4 antidiabetes drug users who did not
improve their plasma glucose levels despite an intravenous
drip infusion of glucose for ≥2 days, but no AI was found inany of them. Therefore, we thought that AI might not be thecause of hypoglycemia in patients using antidiabetes drugs.
In conclusion, the probability of AI was much greater than
we anticipated as a cause of hypoglycemia. When protracted
hypoglycemia of unknown etiology with hyponatremia,
hypotension, and/or eosinophilia is recognized, we recommend that the patient be checked for adrenal function using
the rapid ACTH loading test. There are no untoward side effects, and allergic reactions are extraordinarily rare. ACTH
tests can be performed without monitoring by an advanced
healthcare provider and are less expensive.

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