HYPOGLYCEMIA AS INITIAL PRESENTATION IN PATIENT WITH ISOLATED ACTH DEFICIENCY

Abstract

Objective:

Isolated adrenocorticotropic hormone (ACTH) deficiency is characterized by loss of adrenocorticotropic hormone, resulting in adrenal insufficiency, which can lead to life threatening severe hypoglycemia. We report a case of isolated ACTH deficiency with emphases on presentation, common etiologies, diagnosis, and management.

Methods:

The clinical course in addition to laboratory and imaging results are presented. These include cortisol level, ACTH, other pituitary hormones, insulin tolerance test, pituitary antibodies, and pituitary magnetic resonance imaging.

Results:

A 19-year-old male was brought by ambulance to the emergency department with loss of consciousness and a random blood sugar of 30 mg/dL. Our patient had a barely detectable level of plasma ACTH repeatedly and cortisol <1 μg/dL. There was no involvement of other pituitary hormones. Steroid replacement therapy led to resolution of all symptoms and prevented further episodes of hypoglycemia.

Conclusion:

Isolated ACTH deficiency is a rare condition that is challenging to diagnose and can lead to serious life-threatening problems if unrecognized. Proper management can be achieved with appropriate hydrocortisone supplementation to mimic the normal secretion under both normal conditions and during a state of stress.

INTRODUCTION

Adrenal insufficiency is defined as impaired synthesis and release of adrenocortical hormones. It can be of an adrenal origin (primary), dysfunction or deficiency in secretion of adrenocorticotropic hormone (ACTH) by the pituitary gland (secondary), or interference with the secretion of corticotrophin-releasing hormone at the level of the hypothalamus (tertiary). Isolated ACTH deficiency is categorized as secondary adrenal insufficiency, and is a life-threatening disorder which can present with asthenia, anorexia, unintentional weight loss, and hypoglycemia.

CASE REPORT

A 19-year-old Saudi male presented to King Fahd University Hospital with 2 days history of fever, cough, and a decreased level of conciseness. He was brought by ambulance due to loss of consciousness and was found to have hypoglycemia where random blood sugar (RBS) was found to be 30 mg/dL. He was previously in good health with no significant history of illness during infancy or childhood. However, 3 years prior to this presentation, he started to be fatigued, lethargic, and had a decreased appetite accompanied with weight loss. Moreover, he had repeated episodes of loss consciousness.

On presentation, after initial resuscitation by Red Crescent, he was conscious, alert, and oriented. His vital signs were: blood pressure at 90/48 mm Hg, heart rate at 103 beats/minute, respiratory rate at 22 breaths/minute, and temperature at 37.8°C.

A venous blood gas sample was taken during resuscitation and it showed metabolic acidosis (Table 1). During physical examination, he looked generally ill with normal to lean body build with a height of 164 cm and weight of 51 kg. There was no evidence of hyperpigmentation or postural hypotension. The other laboratory results were within the normal reference range. Hemoglobin was 13.8 g/dL, white blood cells were 5.5 × 10³ μL, platelets were 198 × 10³ μL, and lactic acid was 1.2 mmol/L. Renal function tests were within normal range.

Table 1.

Venous Blood Gas

	Value	Normal range
pH	7.28	7.35–7.45
pCO2, mm Hg	38.8	35–45
pO2, mmol/L	22.3	83–108
Na, mmol/L	144	136–146
K, mmol/L	4.7	3.4–4.5
Ca, mmol/L	1.19	1.15–1.29
Cl, mmol/L	113	98–106
HCO3, mmol/L	17	22–26
sO2, %	36.1	95–99
Anion gap, mmol/L	15	12 ± 4

Abbreviations: Ca = calcium ion; Cl = chloride ion; HCO3 = bicarbonate; K = potassium ion; Na = sodium ion; pCO₂ = partial pressure of carbon dioxide; pO₂ = partial pressure of oxygen; sO₂ = oxygen saturation.

The patient was managed by intravenous “D5 0.45 normal saline” 120 mL/hour. He remained hypotensive even after receiving 1.5 L of normal saline. The provisional diagnosis was made as adrenal insufficiency based on his presenting symptoms of fatigue, lethargy, hypoglycemia, and hypotension. Accordingly, further assessment was performed. Plasma cortisol and ACTH level were measured and were found to be low at <1 μg/dL and 1.15 pg/mL, respectively. He then had a more focused medical examination looking for other signs indicating hypopituitarism. The examination revealed no signs of hypogonadism, hypothyroidism, or growth hormone deficiency. The rest of anterior pituitary function was assessed and results were within normal limits (Table 2).

Table 2.

Hormonal Panel

Hormone tested with unit	Result	Reference range
LH, mIU/mL	2.35	0.57–12.07
FSH, mIU/mL	1.03	0.95–11.95
GH, ng/mL	0.148	0.03–2.47
ACTH, pg/mL	1.15	7.2–63.3
Cortisol, μg/dL	<1.0	3.7–19.4 in am, 2.9–17.3 in pm
TSH, μIU/L	2.685	0.35–4.94
FT4, ng/dL	0.96	0.7–1.53
FT3, pg/mL	2.70	2.3–4.2
PRL, ng/mL	10.60	3.46–19.40
Testosterone, ng/mL	1,006.17	280–1,100

Abbreviations: ACTH = adrenocorticotropic hormone; FSH = follicle-stimulating hormone; FT3 = free triiodothyronine; FT4 = free thyroxine; GH = growth hormone; LH = luteinizing hormone; PRL = prolactin; TSH = thyroid-stimulating hormone.

A pituitary magnetic resonance imaging scan was requested and revealed no evidence of any pituitary lesions (Figs. 1 and 2). The final diagnosis had been established as isolated adrenocortical hormone deficiency. He was started on hydrocortisone treatment at the second day of admission which resulted in a marked improvement within a few days.

Fig. 1.

Pituitary MRI. Sagittal view without evidence of masses or inflammatory process. MRI = magnetic resonance imaging.

Fig. 2.

Pituitary MRI. Axial view with no evidence of masses or inflammatory process. MRI = magnetic resonance imaging.

On further follow-up, insulin-like growth factor 1 level was requested and it was 76.6 ng/mL which is considered low for age and sex (normal, 117 to 323 ng/mL). The patient was sent for dynamic testing with an insulin tolerance test. Upon stimulation, growth hormone came to be within normal range and was stimulated by the hypoglycemia. However, 45 minutes into the test he had symptomatic hypoglycemia with RBS of 32 mg/dL, so the test was ceased and hypoglycemia was managed by D5. However, his cortisol level persisted to be low during the test. He was tested for antipituitary antibodies and other autoimmune diseases and all were negative.

Initially after improvement, the patient was lost to follow-up for a few months and at that time he wasn’t compliant to steroid replacement therapy and he developed an adrenal crisis which was managed accordingly and he resumed his medication afterward with significant improvement.

DISCUSSION

The patient reported here was a previously healthy young adult who presented with loss of consciousness which was related to hypoglycemia. He had undetectable cortisol levels and very low ACTH despite the undetectable cortisol, indicating that glucocorticoid deficiency was secondary to ACTH deficiency.

Isolated ACTH deficiency is a rare disorder. It is characterized by loss of adrenocorticotropic hormone and results in adrenal insufficiency (1). Adrenal insufficiency is defined as impaired synthesis and release of adrenocortical hormones. It is classified into primary, where the dysfunction is within the adrenal glands themselves. Secondary ACTH deficiency happens when the defect is in the pituitary gland secretion of ACTH. Isolated ACTH deficiency is a secondary cause of adrenal insufficiency. It is defined as low or absent cortisol production, despite normal secretion of other pituitary hormones, and the absence of structural defects within the pituitary gland (1).

The clinical presentation of isolated ACTH deficiency is variable and nonspecific. Stacpoole et al (2) reported the major clinical findings in 43 cases which included weakness, fatigue, nauseas and vomiting, anemia, and hypoglycemia. In addition, asthenia, anorexia, and unintentional weight loss were also documented. Isolated ACTH deficiency patients may present with atypical manifestations such as flexion contractures of the legs, muscle atrophy, and recurrent syncope (3). Our patient had fatigue, lethargy, and weight loss with frequent attacks of loss of consciousness. He was hypoglycemic where the RBS was 30 mg/dL.

Hypoglycemia is not completely explained by the impaired adrenaline and cortisol release (4). The hypoglycemia in cortisol deficiency may be due to decreased gluconeogenic enzymes or due to an improper supply to the endogenous gluconeogenic substrates such as alanine and lactate with the presence of compensatory breakdown of fat and ketone production (4). The etiology of isolated ACTH deficiency is thought to be of a pituitary origin and the most common etiologies are due to congenital, auto-immune process (lymphocytic hypophysitis), iatrogenic corticotrope deficiency after prolonged steroid therapy, and incomplete post-partum pituitary infarct (1). There are some other less frequent causes for this disorder such as traumatic head injury, or due to a birth trauma (5). Several cases had reported onset after malignancy and use of chemotherapy or after a course of chronic illness. The age of onset varied between infancy and early childhood and middle age to elderly. During our review of the literature, we found that the onset in young adults was more common in post-partum ladies. Taking into consideration the age and previous unremarkable history of our patient, makes this onset quite rare.

The congenital form of isolated ACTH deficiency is considered very rare with few cases describing an initial onset occurring during the neonatal period and can be extended to occur into the early years of life. It usually carries out an autosomal recessive pattern of inheritance (6). Adult idiopathic isolated ACTH deficiency has been suggested to have a link with lymphocytic hypophysitis or autoimmune processes. This is characterized by a chronic inflammatory process of the anterior pituitary potentially followed by destruction of the tissue (7). It has been linked to several endocrine and nonendocrine autoimmune disorders. The most common association has been reported with Hashimoto thyroiditis and Graves disease. Other associations are with type 1 diabetes, central diabetes insipidus, hypoparathyroidism, and pernicious anemia (1).

In 30% of patients with lymphocytic hypophysitis, antipituitary antibodies were detected (8). On the other hand, several patients who were shown by biopsy to have the autoimmune form of the disease were found to have undetected antibodies. The presence of antipituitary antibodies is nonspecific because it has been described in several other diseases such as Cushing disease, celiac disease, and empty sella turcica syndrome (9). In our patient, anti-pituitary antibodies were negative. Diagnosis of isolated ACTH deficiency was based on the following criteria (10): (1), Evidence of low plasma cortisol and low plasma ACTH, with improper response to stimulation testing. Low dose ACTH stimulation test: it has been shown that using lower levels of ACTH can more accurately detect mild degrees of adrenal insufficiency. A low-dose (1 μg) ACTH stimulation test when administered intravenously results in a cortisol value of >18 mg/dL at baseline or 30 minutes post-ACTH, which indicates normal adrenal function (11). Insulin tolerance test (ITT): it is the gold standard required to establish a diagnosis of ACTH deficiency. The ITT is used to assess the integrity of the hypothalamic-pituitary axis. This test is not advised to be conducted in patients with ischemic heart disease (it is recommended to obtain a baseline electrocardiogram before the test), epilepsy, or in the case of severe cortisol deficiency (12); (2), Lack of other anterior pituitary hormonal deficiencies; (3), Normal hypothalamo-pituitary imaging, with no evidence of a tumor or stalk enlargement; and (4), Intact renin/aldosterone axis.

Just as in our case, several cases were confirmed to have isolated ACTH deficiency with normal initial imaging results (13). The absence of abnormalities on imaging doesn’t exclude the diagnosis of an autoimmune cause and may indicate an early stage of the disease where pituitary changes cannot be identified.

Managing isolated ACTH deficiency depends on the patient’s condition. In an acutely ill state, management is the same as managing a case of adrenal crisis. Blood tests should be ordered prior to administration of corticosteroid therapy, including plasma electrolytes, blood glucose ACTH, and cortisol. Intravenous saline should be prescribed initially; 5% dextrose saline if the patient has a hypoglycemic episode (14). In the case of a vitally stable patient, the ACTH stimulation test can be performed. Clinical improvement like normalizing of blood pressure should be noticed within 6 hours. It is important to identify any precipitating condition such as trauma or infections (14). After 24 hours of hydrocortisone therapy, the doses can be reduced from 100 mg every 6 hours to 50 mg every 6 hours, and then, if possible the intravenous form should be shifted to oral hydrocortisone and titrated until reaching the lowest possible dose where the patient is stable (14).

The possible complications due to isolated ACTH deficiency are variable to the point of being life-threatening if hypoglycemia is not recognized, where a person can end up in a coma leading to death. For example, a case by Suzuki et al (15) reported isolated ACTH deficiency in an elderly person who had also been diagnosed to have a prolonged QT interval; such presentation can lead to fetal arrhythmias (15).

CONCLUSION

In conclusion, isolated ACTH deficiency is a rare condition that is challenging to diagnose and can lead to serious life-threatening problems if unrecognized. The standard of diagnosis is the stimulation test, most often a short ACTH or ITT. Proper management can be achieved with appropriate hydrocortisone supplementation to mimic the normal secretion under both normal conditions and during state of stress.

Abbreviations

ACTH

adrenocorticotropic hormone

ITT

insulin tolerance test

RBS

random blood sugar