INTRODUCTION

Primary adrenal insufficiency (PAI), also called Addison’s disease, is defined by the inability of the adrenal cortex to produce sufficient amounts of glucocorticoids and/or mineralocorticoids. PAI is a severe and potentially life-threatening condition due to the central role of these hormones in energy, salt and fluid homeostasis.¹

We herein report a case of PAI presenting with nonspecific symptoms, which was unrecognized in its early stage. We elucidate the importance of looking for certain signs and laboratory findings that may provide important clues to diagnosis. Early recognition of primary adrenal insufficiency is challenging, so this case highlights the need for clinicians to keep a high index of suspicion for PAI.

CASE DESCRIPTION

A 35-year-old portuguese man with a medical history of cavernous angiom, focal epilepsy and hypothyroidism due to autoimmune thyroiditis, presented to our emergency department (ED) with a 5-month history of intermittent nausea, vomiting, anorexia, repeated episodes of diffuse abdominal pain, marked fatigue and recurrent holocraneal headaches. He reported a history of weight loss in the last 8 months (about 16 Kgs). His mother referred that over the past few months he had experienced several periods of transient confusion with impairment of consciousness levels/obnubilation during which hypoglycemia was detected (lower capillary blood glucose of 44 mg/dL). The patient had sought medical services four times since the onset of symptoms. A review of the records revealed that he had low blood pressure, transient acute kidney injury and persistent normocytic anemia, hyponatremia and hyperkalemia. A fecal occult blood test was negative and he had also performed an upper gastrointestinal endoscopy and a cranial, thoracic, abdominal and pelvic computed tomography that were normal except for the cavernous angiom already known. He was treated for a depressive disorder and his psychiatric medication was adjusted six days before he went to our ED because he felt unable to do anything, stating that he didn’t have the strength to eat or to do his hygiene. He denied fever, diarrhea, jaundice, heartburn, visible blood loss, head injury, visual disturbances, syncope, precordial pain, respiratory or urinary complaints, past history of tuberculosis, alcohol, tobacco or illicit drug use. He was taking levothyroxine, levetiracetam, pantoprazol, clomipramine, mirtazapine, risperidone and amisulpride.

On admission the patient was conscious but with verbal response lentification and a disorganized speech, afebrile, normotensive (120/83 mmHg) and his pulse was 73 bpm. He was 67 Kg in weight and 184 cm in height with a body mass index of 19.79 Kg/m² and exhibited generalized hyperpigmentation since the previous year. The rest of the physical examination was unremarkable.

To assess his symptoms initial evaluation included a complete blood count and biochemical profile (Table 1). Electrocardiography and chest radiograph were normal. A cranial computed tomography was ordered with no new findings.

In view of his symptoms, darker complexion, normocytic anemia, hypotonic hyponatremia, hyperkalemia, history of hypoglycemia and low blood pressure records he was admitted to a medical ward considering the diagnostic hypothesis of PAI.

Additional laboratory investigations (Table 2) were performed, which confirmed the diagnosis of PAI.

The recent abdominal computed tomography showed no calcification, enlargement or surrounding mass lesion in the adrenal glands. He was negative for HIV testing and 17-OH-progesterone was normal. Autoantibodies against 21-hydroxilase and plasma very long chain fatty acids were performed, but results are not yet available. However, in this case, because of his history of autoimmune thyroid disease and its known association with other autoimmune endocrine disorders, autoimmune adrenalitis would be the most likely cause of PAI. Other autoimmune disorders were excluded. After discussion of the case with Endocrinology, the patient was started on hydrocortisone 100mg intravenous every 8 hours and due to clinical and electrolyte improvement, the next day hydrocortisone was weaned to oral dose of 20 mg in the morning, 10 mg at lunch and 10 mg in the evening. He also started fludrocortisone replacement therapy with 0.1 mg in the morning. His clinical status greatly improved and was discharged under oral hydrocortisone 10 mg-5 mg-5 mg per day. On follow-up at 25 days he was tapering off psychiatric medication, showing significant improvement. The patient had gained weight, pigmentation had reduced and his blood pressure, electrolytes, haemoglobin value and blood sugar were within normal limits. He was educated about the importance of maintaining lifelong hormone therapy with glucocorticoids and mineralocorticoids and how to administer intramuscular hydrocortisone in case of emergency.

DISCUSSION

PAI is a rare endocrine disease with a reported prevalence of about 100 to 140 cases per million and an incidence of 4:1 000 000 per year in Western societies.¹ A multicentre retrospective study examined adult patients diagnosed with PAI in 12 portuguese hospitals and found a slight predominance of the female gender and a mean age at diagnosis was 33.6+19.3 years.²

The presenting signs and symptoms of PAI are based on the degree of deficiency of glucocorticoids and mineralocorticoids. Its onset is often insidious, including nonspecific features like fatigue, anorexia, weight loss, nausea, vomiting, abdominal pain, musculoskeletal pain, depression and confusion. As a result, there is a delay in diagnosis because complaints can easily be attributed to other causes, leading to an erroneous diagnosis.¹ Our patient was seen by a variety of physicians before PAI was diagnosed because his complaints strongly suggested a gastrointestinal, psychiatric or neoplastic disease. After an initial investigation, depression was considered as a possible cause for his constitutional syndrome and he started on medication. The concept of Addison’s encephalopathy was introduced by Klippel in 1899, noting that neuropsychiatric symptoms are common in PAI. From 64% to 84% of patients with Addison’s disease present with or experience accompanying psychiatric symptoms.³ PAI should be considered in all patients with any of the symptoms listed above. However, the concomitant presence of certain findings, particularly skin hyperpigmentation, hypotension, hyponatremia, hyperkalemia, anemia and hypoglycemia, provide important clues leading to a higher suspicion of PAI.^1,4In this patient the clinical picture, physical signs and laboratory abnormalities supported the diagnosis.

The “gold standard” for the diagnosis of PAI is Synacthen test that consists of measuring cortisol levels before and 30 or 60 minutes after intravenous administration of 250 µg corticotrophin as bolus injection. Peak cortisol levels below 18 µg/dL indicate PAI. However, if morning cortisol concentration is significantly low (<5 µg/dL) in combination with a plasma ACTH concentration elevated more than 2-fold above the upper limit of the reference interval, the diagnosis of PAI is highly likely and a stimulation test is not required. Furthermore, an elevated plasma renin activity or concentration in combination with an (inappropriately) normal or low serum aldosterone concentration is suggestive of PAI.¹ In our clinical case, as the basal cortisol and ACTH values were absolutely unequivocal, it was sufficient to make the diagnosis of PAI.

The most common cause of PAI in adults is autoimmune destruction of the adrenal cortex. PAI is commonly associated with other autoimmune disorders, especially auto-immune thyroid disease, which is seen in 25% of males with PAI.¹ Our patient is very likely to have these two medical conditions, which means that we are possibly in the presence of an autoimmune polyendocrine syndrome type 2 (APS-2). The onset of APS-2 typically occurs in young adulthood and the affected patients have courses characterized by at least two of the following three endocrinopathies: type 1 diabetes, autoimmune thyroid disease and Addison’s disease.⁵

Monitoring glucocorticoid replacement relies primarily on clinical assessment, so symptoms and signs of over-replacement and insufficient dose should be sought. Also patients with confirmed aldosterone deficiency should be monitored based on clinical evaluation and blood electrolyte measurements. Plasma renin activity or renin substrate in the upper reference range is a useful maker for a correct mineralocorticoid dose, while using ACTH levels to adjust glucocorticoid replacement is clinically known to lead to over-replacement. Measurement of cortisol, not routinely, can be useful to obtain evidence of adequate cortisol uptake.¹

Patients should be instructed about the importance of therapeutic compliance.

Quadro I

Main laboratory results carried out in emergency department

Quadro II

Laboratory investigations performed in medical ward

  BIBLIOGRAFIA  

REFERENCES

1. Bornstein SR, Allolio B, Arlt W, Barthel A, Don-Wauchope A, Hammer GD, et al. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101(2):364-389. doi: 10.1210/jc.2015-1710.

2. Ferreira L, Silva J, Garrido S, Bello C, Oliveira D, Simões H, et al. Primary adrenal insufficiency in adult population: a Portuguese Multicentre Study by the Adrenal Tumours Study Group. Endocr Connect. 2017;6(8):935-942. doi: 10.1530/EC-17-0295.

3. Johnstone PAS, Rundell JR, Esposito M. Mental Status Changes of Addison’s Disease. Psychosomatics. 1990;31(1):103-107. doi: 10.1016/S0033-3182(90)72226-8.

4. Barnett AH, Donald RA, Espiner EA. Patients presenting with Addison’s disease need not be pigmented. Postgrad Med J. 1982;58(685):690-692. doi: 10.1136/pgmj.58.685.690.

5. Husebye ES, Anderson MS, Kämpe O. Autoimmune Polyendocrine Syndromes. N Engl J Med. 2018;378(12):1132-1141. doi: 10.1056/NEJMra1713301.