Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a disease without a definite, unambiguous aetiology. An estimated 10 000 – 20 000 people in Norway are affected, to various degrees (4). One trigger for conditions are infectious diseases (4), and our patient was told this was the cause in her case.
In addition to inexplicable exhaustion, which substantially reduces their functional level compared with previously, patients with this condition have several different physical and cognitive symptoms as a rule. These include orthostatic hypotension, vertigo, general weakness, musculoskeletal pain and nausea (4). Similar symptoms also often occur in patients with adrenal insufficiency (5).
Chronic fatigue syndrome/myalgic encephalomyelitis is an exclusion diagnosis, without biological markers, and it should only be made after a thorough review of the patient’s history of illness, a clinical examination and supplementary tests. Other physical and mental illness that can explain the symptoms must be excluded, and defined diagnostic criteria must be used (4).
Among the differential diagnoses that must be excluded is adrenal insufficiency. This can be done by measuring s-cortisol in the morning – cortisol is among the recommended blood tests in the Norwegian Directorate of Health’s guide (4). If there is still suspicion of adrenal insufficiency, testing with synthetic adrenocorticotropic hormone (ACTH) can be performed. With secondary (pituitary) adrenal insufficiency, the test can be used if the insufficiency has lasted for more than about six weeks. A rise in cortisol to less than 500 nmol/l after 30 minutes has traditionally been perceived as pathological. With the new, specific immunoassays for cortisol, the normal limit will be lower (l). The test is traditionally carried out with supraphysiological doses of synthetic ACTH (250 μg), which with partial adrenal insufficiency may yield false-positive results (6).
Studies indicate dysfunction in the hypothalamus-pituitary-adrenal axis, resulting among other things in a reduction in the cortisol level in patients with CFS/ME. Cognitive treatment may increase the level of cortisol and is regarded as first-line therapy for patients with the condition. However, treatment with corticosteroids is not recommended for these patients (7) – (9).
In a Norwegian retrospective study in which 365 patients with suspected CFS/ME were assessed by neurologists, 48 (13.2 %) received the diagnosis and one was found to have adrenal insufficiency (10).
Pituitary adenomas are benign neoplasms with an incidence of about 4.0 per 100 000 per year (11). Adenomas under 10 mm are called microadenomas, those over 10 mm are called macroadenomas. Of all detected macroadenomas, 80 % are non-hormone-producing. Hypopituitarism in patients with macroadenomas may be caused by pinching of the pituitary stalk, compression of hormone-producing tissue in the hypophysis or affection of the hypothalamus (12, 13).
Non-hormone-producing pituitary adenomas are most commonly found by chance, so-called incidentalomas, through MRI/CT scans of the head, but may also have their onset with loss of vision or hypopituitarism. Headache occurs in 40 – 60 % of the patients and may be due to stretching of the meninges and occasionally to increased intracranial pressure (12, 13). Our patient had a constant headache, loss of vision and severe hypopituitarism with low levels of ACTH, TSH and gonadotropins.
Pituitary adenomas often grow slowly. The MRI scan of the head was described as normal when she received the diagnosis CFS/ME, and it is therefore probable that the pituitary adenoma developed along the way. The original MRI scans are unfortunately not available for further scrutiny.
With primary adrenal insufficiency, hyponatraemia is the most common laboratory finding (in 70 – 80 %), followed by hyperkalaemia (in 30 – 40 %). With secondary adrenal insufficiency (hypopituitarism), the renin-angiotensin-aldosterone axis is intact and hypotension and electrolyte imbalance less usual. Hyponatraemia may occur in these patients, particularly in stress situations where the cortisol response is poor, while ADH secretion is intact. This may yield a picture of a SIADH condition (5). Our patient developed severe hyponatraemia during her stay in hospital, and as s-sodium was not measured before admission, it is not certain how long she had had hyponatraemia. Figure 3 illustrates the mechanisms for regulating water and salt balance.
Secondary adrenal insufficiency can be excluded if s-cortisol in a morning sample is at the upper reference limit. In cases of doubt, the test can be supplemented with a synacthen test or insulin tolerance test, which also tests function in the growth hormone axis. In cases of partial insufficiency, the synacthen test may yield a false positive response, but is preferred by many because it has few contraindications and is simple to perform. Low levels of T4 and low or normal levels of TSH must always arouse suspicion of central hypothyroidism (13). This may have been overlooked in our patient prior to the hospitalisation in question. S-cortisol was not measured as part of the workup for CFS/ME.
Specially adapted MRI scanning is used for diagnostic imaging of pituitary adenomas. Contrast is administered, and high definition series used over the hypophysis in coronal and sagittal plane, which shows the relationship of the tumour to the chiasma and other important surrounding structures. If MRI examination is contraindicated, a CT scan is an alternative. The visual function must be assessed by an ophthalmologist if it is suspected that the pituitary adenoma is affecting the optic nerve decussation or other parts of the optic paths.
Surgery is the first line of treatment for patients with non-hormone-producing macroadenomas. Surgery is indicated in cases of reduced visual function and pituitary apoplexy with impaired vision or ophthalmoparesis (indication for emergency aid). The prolactin level must be measured before the procedure because prolactinomas must almost always be treated medicinally. If there is no clear indication for immediate surgical intervention, one should also wait for the growth hormone and IGF-1 analyses, because data indicate a better outcome for an operation after preliminary treatment with somatostatin analogue (14).
Since the chances of curing hypopituitarism are only marginally greater than the risk of exacerbating the condition with surgery, hypopituitarism alone is no strong indication for surgery (15). Transsphenoidal surgery with microscope and/or endoscope is the preferred surgical method. If the patient cannot undergo surgery, radiotherapy may be an option. The main objective of the treatment is to preserve the visual function. Surgery results in improved visual function in approximately 80 % of patients, often within a few days of the procedure (12, 13). Our patient experienced a subjective normalisation of her vision and end to headache the same day as she underwent surgery.
Glucocorticoid deficiency can be life-threatening, and on clinical suspicion substitution therapy must be started. If possible, hormone analysis should be performed – primary cortisol, TSH, free T4 and prolactin, possibly also adrenocorticotropic hormone (ACTH), luteinising hormone (LH), follicle-stimulating hormone (FSH), sexual hormone-binding globulin (SHBG), growth hormone, IGF-1, oestradiol (women), testosterone (men) – before starting the therapy. Hypothyroidism is treated with levothyroxine. Thyroxine increases the metabolism and can lead to adrenal crisis, so thyroxine substitution treatment should only be given after glucocorticoid substitution treatment (13). Our patient received a low dose of levothyroxine for two weeks before she started on cortisone acetate. This could have triggered an adrenal crisis. With most patients, appropriate hormone substitution treatment can almost normalise quality of life, morbidity and mortality associated with hypopituitarism (16).
The daily cortisone requirement increases in the event of infections, fever or stress. The daily dose should therefore be doubled or tripled. In case of signs of adrenal insufficiency, fluid and hydrocortisone should be administered intravenously. After the acute phase, the dose is rapidly reduced to the normal maintenance dose. All patients should be equipped with a Norwegian steroid card, which contains information of importance to medical personnel who meet the patient.