Central adrenal insufficiency: who, when, and how? From the evidence to the controversies - an exploratory review

ABSTRACT Central adrenal insufficiency (CAI) is a life-threatening disorder. This occurs when ACTH production is insufficient, leading to low cortisol levels. Since corticosteroids are crucial to many metabolic responses under organic stress and inflammatory conditions, CAI recognition and prompt treatment are vital. However, the diagnosis of CAI is challenging. This is not only because its clinical presentation is usually oligosymptomatic, but also because the CAI laboratory investigation presents many pitfalls. Thus, the clarification of when to use each test could be helpful in many contexts. The CAI challenge is also involved in treatment: Several formulations of synthetic steroids exist, followed by the lack of a biomarker for glucocorticoid replacement. This review aims to access all available literature to synthesize important topics about who should investigate CAI, when it should be suspected, and how CAI must be treated.

A Pitfall in the Differential Diagnosis of Hyponatremia / General Medicine

We report a case of a 75-year-old female, with a known history of Hashimoto’s disease, who was admitted with anorexia, nausea and vomiting. Laboratory data revealed hyponatremia and hypothyroidism. Despite thyroid hormone replacement with synthetic thyroxine, the patient had persistent hyponatremia. Further investigations revealed secondary adrenal insufficiency but otherwise normal pituitary function, based on a rapid adrenocorticotrophic hormone (ACTH) test as part of a combined anterior pituitary stimulation test. She was diagnosed with isolated ACTH deficiency (IAD) with concomitant Hashimoto’s disease. Adrenal insufficiency should be considered in patients with hypothyroidism and persistent hyponatremia. In patients with Hashimoto’s disease who are found to have concomitant hypoadrenalism, IAD should also be suspected after primary adrenal insufficiency is ruled out.

A Case with Empty Sella Syndrome Combined with Multiple Anterior Pituitary Hormone Deficiencies Presenting as Hypoglycemic Coma / 고신대학교의과대학학술지

A 55-year-old male was admitted to emergency department with a hypoglycemic shock of unknown origin. He was presented with tonic seizure activity after admission. Initial diagnostic procedure could exclude diabetes mellitus, drug side effects, and exogenous insulin application. Detailed evaluation of the patient's history revealed that the patient had experienced repeated hypoglycemic episodes for 2 years. He was diagnosed with hypothyroidism six years ago. Initial laboratory investigations revealed hypoglycemia, hyponatremia, and low plasma cortisol level (0.18 microg/dL). Sellar magnetic resonance imaging showed empty sella. Replacement therapy with hydrocortisone resulted in the improvement of clinical symptoms. Combined pituitary stimulation test with exception of hypoglycemia induced growth hormone and cortisol stimulation test was performed. The response of thyroid stimulating hormone, prolactin, follicle-stimulating hormone, and luteinizing hormone was normal. We report the case of empty sella syndrome associated with hypoglycemic shock due to with multiple anterior pituitary hormone deficiencies.

A Case Report of Isolated ACTH Deficiency with Severe Dysphasia / The Japanese Journal of Rehabilitation Medicine

The following report illustrates a rare case of dysphagia caused by secondary adrenal insufficiency in a patient with isolated ACTH deficiency. A 76-year-old man with progressive appetite loss, weight loss and general fatigue was hospitalized due to dehydration, aspiration pneumonia and hypoglycemia. He was unable to stand and walk by himself. His serum cortisol and ACTH levels were both low. An endocrinological examination resulted in a diagnosis of isolated ACTH deficiency. Following the administration of 15mg of glucocorticoids daily, his symptoms diminished without dysphagia. Furthermore, we investigated his swallowing function using a videofluoroscopic examination of swallowing (VF). The VF showed an impaired laryngeal movement as well as an upper esophageal opening and severe aspiration without a delay in his swallowing reflex. Oral intake was judged to be impossible, but his swallowing function gradually improved and he was able to resume eating all of his meals 2 months after treatment. Dysphagia is not a common symptom in ACTH deficient patients but a few similar cases have been reported. The swallowing function of the patients in these cases was not evaluated in detail, so we evaluated this case according to the results of the VF and the patient's process of recovery. Careful monitoring of swallowing function and appropriate treatment for both dysphagia and adrenocortical failure are required for the recovery of such patients. In conclusion, practitioners should be wary of isolated ACTH deficiency in elderly patients with progressive weight loss and dysphagia.

Isolated adrenocorticotropic hormone deficiency associated with empty sella syndrome / 대한내과학회지

Isolated adrenocorticotropic hormone (ACTH) deficiency is an uncommon disorder for which the pathogenetic mechanism has not yet been identified. It has been reported that isolated ACTH deficiency (ICD) may be accompanied by deficiencies in other pituitary hormones; impaired growth hormone (GH) secretion was noted in 20 to 30% of ICD patients. Here, we describe a female patient with isolated ACTH deficiency accompanied by empty sella syndrome presenting as hypoglycemia, which was confirmed via various endocrine tests and magnetic resonance imaging (MRI) of the sella turcica. The patient's symptoms improved rapidly with prednisolone therapy and, during follow-up, her previously impaired GH response to provocative stimuli and high TSH levels were corrected by glucocorticoid replacement alone. However, treatment failed to normalize plasma IGF-1 levels, suggesting that physiological cortisol levels are necessary for a normal plasma GH response to provocative stimuli.

Clinical and Hormonal Analysis of Five New Cases and Eight Previously Reported Cases of Isolated ACTCH Deficiency in Korea / 대한내분비학회지

Isolated ACTH deficiency is an uncommon disorder, which is defined by low cortisol production with low or normal plasma ACTH levels and no other pituitary abnormalities. We report five new cases of this disorder, and summarize the clinical and hormonal features of 8 previously reported cases in Korea plus 5 new cases. 1) The clinical manifestations of isolated ACTH deficiency are variable, non-specific and similar to those seen in adrenocortical insufficiency of any cause, the age of patients ranged from 21 to 66 years old with an average age of 46 years, and the male to female ratio was 10:3. 2) Hyponatremia and hypoglycemia were commmon laboratory findings, so the presence of unexplained hyponatremia or hypoglycemia should always warrant consideration of the diagnosis of isolated ACTH deficiency. 3) 3 of 13 patients accompanied by empty sella suggesting selective destruction of pituitary ACTH producing cells. 4) ACTH response to exogenous CRH or vasopressin was not elicited in all tested cases, suggesting pituitary disorders. 5) Most patients showed dramatic response with oral predinisone. In conclusion, when there are unexplained general weakness, fatigue, weight loss, nausea, vomiting, hypoglycemia, or hyponatremia, isolated ACTH deficiency should be excluded. Immunologic and pathologic studies, and hormonal evolution with glucocorticoid treatment are needed to understand the pathogenesis of isolated ACTH deficiency.

A Case of Isolated ACTH Deficiency with Rapid Deterioration / 대한내분비학회지

Isolated ACTH deficiency is a rare disorder, and usually characterized by its chronic course. The 59 year-old woman patient who had been healthy until 2 months ago, admitted because of abdomial pain, general weakness and loss of weight about 12kg for 2 months. She looked a little pallor but color of skin was not remarkable. Blood pressure, serum electrolyte, and glucose on admission were within normal range. Serum calcium was elevated with the value of 12.6mg/dL, which was normalized after hydration. Cortisol response to RI induced hypoglycemia did not show any response. Anterior pituitary hormone except ACTH showed normal response during combined pituitary hormone stimulation test. These clinical and laboratory finding reveals that isolated ACTH deficiency was developed in a short term period. There were no abnormalities in sellar MRI except pineal cyst. Her complaints were disappeared dramatically after hydroccetisone replacement at 4th. hospital day. Here we report a case of isolated ACTH deficiency, which was rapidly developed, with hypercalcemia, abdominal pain, and loss of weight about 12kg for 2 months.

A Case of Hypocortisolemia Presented by Short Stature / 대한소아내분비학회지

Isolated ACTH deficiency is a rare cause of secondary adrenocortical insufficiency. The clinical presentation can be similar to that of primary adrenal insufficiency, but most of them may be nonspecific. A female patient of 25 months of age, complainig short stature, showed hypocortisolemia without ACTH & cortisol stimulation by insulin-induced hypoglycemia test. All the other hormone state was normal. Left hand AP view revealed delayed bone age(3 month) compared with chronological age. No radiologic abnormality was found in sella MRI and adrenal CT. Here we report a case of isolated ACTH deficiency presented by short stature.

A Case of Isolated ACTH Deficiency Manifestated by Atrial Fibrillation and Hypoglycemia / 대한내분비학회지

Isolated ACTH deficiency is a rare cause of secondary adrenocortical insufficiency caused by the defect of synthesis or release of ACTH in pituitary gland. The clinical presentation can be simiilar to that of primary adrenal insufficiency, but there is a greater tendency for hypoglycemia and absence of hyperpigmentation. The patient, 80 year-old female, was admitted in chief complaint of deteriorated mental states. On admission, serum sodium was 127mEq/L, potassium 4.4mEq/L, blood glucose 27mg/dL and on routine E.C.G. was atrial fibrillation was revealed. The basal morning serum cortisol level was 9.97 pg/dL it dosent respond to insulin-induced hypoglycemia enoughly, but other pituitary functions were intact in pituitary cocktail stimulation test. In CRH stimulation test, there was no remarkable response in serum ACTH and cortisol level. Brain MRI failed to reveal any anatomic abnormalities of the sellar or suprasellar area consistent with the defect of pituitary ACTH secretion. This case was a isolated ACTH deficiency, So, we conclude that associated with atrail fibrillation and hypoglycemia.

A Case of Isolated ACTH Deficiency Accompanied by hyperprolactinemia / 대한내분비학회지

Isolated ACTH deficiency is a uncommon disorder causing secondary adrenocortical insufficiency. Less than 200 cases have been reported in the world. The major clinical manifestations are hypoglycemia, weight loss, hypotension, anemia, weakness, nausea, inability to excrete water load, and hyponatremia. A 56-year-old male was admitted because of weakness, fatigue, nausea and vomiting. He was pallor and not associated with hyperpigmentation. The basal plasma ACTH and cortisol levels were 8.30 pg/ml and 0.6 ug/dl. The serum cortisol did not response to rapid ACTH stimulation test. On combined pituitary stimulation test, the cortisol did not response to insulin-induced hypoglycemia. Other anterior pituitary hormones showed normal responses except elevated prolactin level. Six months after glucocorticoid replacement therapy, the elevated basal prolactin level returned to normal. Brain MRI did not show any anatomic abnormalities of the sellar and suprasella area. We report a case of isolated ACTH deficiency accompanied by hyperprolactineia, which respond to glucocorticoid replacement therapy.

A Case with Isolated ACTH Deficiency / 대한내분비학회지

Isolated ACTH deficiency is a rare cause of secondary adrenocortical insufficiency. Adrenal crisis in isolated ACTH deficiency is less common compared to primary adrenal insufficiency, but isolated ACTH deficiency is an important cause of hypoglycemia. Recently we experienced a 41-year-old man admitted because of mental confusion. On admission, plasma glucose and sodium concentration were 1.7, 132 mmol/L, respectively. Basal plasma ACTH and cortisol levels were low and other pituitary hormone showed normal response to combined pituitary stimulation test except growth hormone. Plasma ACTH concentration remained low even after intravenous injection of ovine corticotropin releasing factor. It suggest that the defect of ACTH secretion was apparently due to intrinsic pituitary rather than hypothalamic disease. The sellar CT showed the fossa to be filled by cerebrospinal fluid. After treatment with glucocorticoid, he had no further evidence of hypoglycemia and hyponatremia. In conclusion, we report a case of isolated ACTH deficiency with empty sella.

A Case of Isolated ACTH Deficiency / 대한내분비학회지

solated ACTH deficiency is a very uncommon cause of hypoadrenocorticism, with less than 200 cases reported in the literatures. The clinical presentation can be similar to that of primary adrenal insufficiency, but there is a greater tendency for hypoglycemia and absence of hyperpigmentation. The diagnosis is established by demonstrating hypocortisolism with undetectable serum levels of ACTH, normal adrenal responsiveness to prolonged ACTH infusion, and an absent ACTH response to insulin-induced hypoglycemia. Other endocrine function is normal.We experienced a case of isolated ACTH deficiency in 34 years old female who was admitted due to fever and drowsy mentality.So we present this case with a review of literatures.