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In occasional patients with low adrenal cortical or thyroid function, the main symptoms are musculoskeletal1, 2. Indeed, when the features are those of a myopathy, the patient is likely to be seen first by a neurologist rather than an endocrinologist, as happened in the following two cases.
A boy of 13 was admitted with a 2-year history of muscle cramps. Serum creatine kinase was 270 U/L (reference range 25-200). Electromyographic findings were normal but muscle biopsy (vastus lateralis) showed atrophic fibres and intermediate type 2c fibres. Because of recent episodes suggestive of postural hypotension the endocrine evaluation focused on possible adrenal cortical hypofunction. Serum cortisol was very low at 95 nmol/L (reference range 160-580), plasma aldosterone was slightly depressed at 48 pmol/L (56-360) and serum corticotropin was very high at 35.6 pmol/L (2.2-13.3). Adrenal cortex antibody was present in a titre of 1:16. Addison's disease was diagnosed and he was started on cortisone acetate 37.5 mg/day and fludrocortisone 50-100 μg/day. After several months' treatment the muscle cramps were no better and the patient was re-evaluated. He proved to have primary hypothyroidism in addition to the adrenal failure—free thyroxine (FT4) 12 pmol/L (reference range 11.7-24.6), basal thyrotropin (TSH) 6 mU/L (0.23-4.0), TRH-stimulated TSH 40 mU/L (5-25). Thyroid microsomal antibodies were present at 1:400; thyroglobulin antibody was not detected. On sonography the thyroid gland was atrophic. When L-thyroxine 100 μg/day was added to the steroid replacement therapy, the cramps disappeared.
A bricklayer aged 45 was admitted with a 5-year history of asthenia, myalgias and cramps in the legs; lately his symptoms had included poor memory and apathy, and vitiligo had appeared. At the age of 35 he had been investigated for similar symptoms and Hashimoto's thyroiditis had been diagnosed, on the basis of a high TSH and positive thyroglobulin and thyroid microsomal antibodies. Taking L-thyroxine 100 μg/day he had then been well for 5 years. Thereafter the symptoms had returned, and in subsequent years evaluations by internists, orthopaedic surgeons, neurologists and psychologists had been unrewarding. Seemingly the possibility of adrenal failure had been considered, because serum cortisol was measured on one occasion, but the result had been normal (233 mmol/L, reference range 193-666).
When referred to us the patient had no abnormal physical signs; blood pressure was 95/60 mmHg. Findings on electromyography and muscle biopsy (vastus lateralis) were normal. Serum creatine kinase was slightly raised at 209 U/L and serum potassium was 5.0-5.3. Morning serum cortisol fluctuated from low-normal 152 mmol/L to normal and responded normally to 250 μg intravenous tetracosactrin with a peak of 588 mmol/L. Adrenal cortex antibodies were present at a titre of 1:64. As well as thyroid microsomal antibody, thyroglobulin and thyroid peroxidase antibodies were positive. We diagnosed polyglandular autoimmune syndrome type II (PGA—II) and added oral cortisone acetate (37.5 mg/day) to the thyroxine therapy. However, the patient did not improve. Therefore we asked him to stop all treatment for 8 weeks and re-evaluated him. We confirmed the primary hypothyroidism (basal TSH 4.3 mU/L; TRH-stimulated TSH 35 mU/L) and borderline hypocortisolism (baseline 150-179 nmol/L; peak after tetracosactrin 560). We also found frank hyperreninaemic hypoaldosteronism (renin 0.57-0.65 nmol/L [reference range 0.16-0.44]; aldosterone 20-35 pmol/L [56-360]. A cause-and-effect relation between hypoaldosteronism and the symptoms is indicated by the disappearance of symptoms with fludrocortisone therapy (Figure 1).
In primary adrenal insufficiency, weakness and fatigue are universal while muscle or joint pains occur in 6-13% of patients1. Investigations of muscle usually show nothing abnormal. In hypothyroidism the features can be similar2, but serum creatine kinase is often raised and electromyographic and muscle biopsy findings are more likely to be abnormal. The two patients here had Schmidt's syndrome—coexistent adrenal and thyroid failure—in the context of PGA—II. PGA—II can include specific neuromuscular disorders such as myasthenia gravis, which we excluded in these cases.
Our patients show the variable spectrum of symptoms in the non-classic presentation of PGA—II. In patient 1, the sole symptom was muscle cramps; in patient 2, cramps were associated with myalgias, weakness and latterly neuropsychological disturbances. In patient 2, myalgias occurred twice—the first time when he was hypothyroid, the second time when he was hypoaldosteronaemic and euthyroid. This fact leads us to another consideration. We show that, even though the same two endocrine glands were functionally impaired, muscle symptoms seem to have had different origins. Patient 1, despite the long duration of symptoms, had normal muscle histology, whereas patient 2 had the histological appearances previously reported in hypothyroid patients, who present with myopathy4.
Adrenal insufficiency is the most frequent cause of hyperreninaemic hypoaldosteronism5, of which hyper-kalaemia is a hallmark. The relapses of neuromuscular symptoms in patient 2 coincided with moderate increases in serum potassium. While we do not know the reason for his hypersensitivity to small changes in kalaemia, it does seem that hypoaldosteronism tends to prevail over hypocortisolism. In a few cases of Addison's disease the autoimmune damage centres on the aldosterone-producing layer (zona glomerulosa) rather than all three layers of the adrenal cortex6.
In conclusion, we underscore the necessity of a thorough endocrine investigation for otherwise unexplained neuromuscular disturbances. Early recognition will be helped by awareness that the muscle symptoms can arise with only marginally raised serum potassium, that such complaints can for a long time be the only feature of adrenal insufficiency and that aldosterone deficiency may outweigh the importance of cortisol deficiency.