Background

Myasthenia gravis (MG), an autoimmune disease caused by the blockade of nicotinic acetylcholine receptors in the junctions between the nerve and muscle by antibodies, is the most common disorder of neuromuscular transmission. More than 50% of MG patients present with ptosis and diplopia, and approximately 15% present with bulbar symptoms, including fatigable chewing, dysphagia, and dysarthria [1]. MG has well-known links with various autoimmune diseases, such as Hashimoto’s disease, Graves’ disease, rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes mellitus [2, 3]. However, case reports of coexistent MG and Addison’s disease are rare.

In this study, we report a rare case of MG in a patient who presented with mild hyperkalemia, which finally led to a diagnosis of MG with primary adrenal insufficiency. We succeeded in diagnosing primary adrenal insufficiency early by considering mild hyperkalemia, which is easily neglected in clinical practice.

Case presentation

A 57-year-old Chinese woman who was a carrier of the hepatitis B and C viruses and who had a 2-year history of MG was receiving treatment with oral Mestinon (pyridostigmine 120 mg daily), which controlled her symptoms well (minimal bilateral ptosis, especially in the morning, and proximal muscle power of 4/5). The diagnosis of MG was verified by the presence of high levels of immunoglobulin G antibodies directed against acetylcholine receptors (54.23 nmol/L). The stimulation single fiber electromyography recorded from orbicularis oculi muscle showed abnormal results (MCD: 180 s), and repetitive nerve stimulation showed no decremental response. A chest computed-tomography (CT) scan showed a thymoma of about 3.2 cm.

She presented with a 7-day history of poor appetite and progressive muscular weakness. Acute exacerbation of MG was initially considered by the neurologist but the muscle weakness did not improve in spite of an increased Mestinon dose to 360 mg daily. She was referred to the nephrology department for further assessment because the laboratory data showed an electrolyte imbalance. Such symptoms such as nausea, vomiting, diarrhea, tarry stool, and lower extremity numbness were absent. There was no history of recent strenuous exercise or diuretic use.

On admission, physical examination revealed clear consciousness and symmetrical weakness of the lower extremities. The following laboratory findings were recorded: blood pressure, 116/64 mmHg; heart rate, 82 beats/min; respiratory rate, 22 breaths/min; and body temperature, 36.8 °C. Moreover, a generalized skin pigmentation without long-term exposure to sunlight was noted. The remainder of the physical examination was unremarkable.

The results of the biochemical analyses are shown in Table 1. The most prominent initial findings were mild hyperkalemia (5.6 mEq/L) and mild hyponatremia (128 mEq/L). Serial urinalysis during admission indicated a decreased K+ excretion rate (transtubular potassium gradient [TTKG] = 2.64; urinary K+–creatinine ratio = 6.4 mmol/mmol). Based on the findings of hyperkalemia with low urine potassium secretion, low aldosterone action was highly suspected. Subsequent hormone profiling revealed normal thyroid-stimulating hormone levels (2.99 μg/dL), an elevated renin concentration (74.5 pg/mL), and low aldosterone (22.24 pg/mL), and cortisol levels (4.65 μg/dL) (Table 1). Accordingly, adrenal insufficiency was diagnosed using the flow chart of hyperkalemia differentiation (Fig. 1). Moreover, the patient’s elevated adrenocorticotropic hormone level (84.4 pg/mL) supported the diagnosis of primary adrenal insufficiency. Magnetic resonance imaging revealed bilateral shrinkage of the adrenal glands, confirming our diagnosis (Fig. 2). Because of the underlying disease of MG, autoimmune adrenalitis was highly suspected, and this was proven by 21-hydroxylase antibody positivity. Thereafter, the final diagnosis was primary adrenal insufficiency due to autoimmune adrenalitis.

Table 1 Laboratory data at admission
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Fig. 1
figure 1

Schematic illustration of the recommended diagnostic approach to hyperkalemia with low renal potassium secretion rate [4,5,6]. Abbreviations: CCD cortical collecting duct, ECF extracellular fluid, Aldo aldosterone, CAH congenital adrenal hyperplasia, ENaC epithelial sodium channel, NSAID nonsteroidal anti-inflammatory drugs, PHA pseudohypoaldosteronism, MR mineralocorticoid receptor

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Fig. 2
figure 2

Abdominal magnetic resonance imaging revealed the relatively small size of the bilateral adrenal gland (arrow)

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Fludrocortisone (0.2 mg daily) was prescribed as mineralocorticoid supplementation. The patient’s serum electrolyte levels normalized, and her general weakness improved. Therefore, she was discharged with oral fludrocortisone (0.2 mg daily) treatment. At the 2-month follow-up, her serum K+ concentration was 3.68 mEq/L.

Discussion

Primary adrenocortical insufficiency (also termed Addison’s disease) is caused by an impaired ability of the adrenal cortex to secrete glucocorticoids and mineralocorticoids, and secondary adrenal insufficiency is caused by hypothalamic–pituitary axis suppression. Adrenocortical insufficiency must be presumptively considered in the presence of a broad spectrum of patient symptoms (weight loss, abdominal pain, nausea, vomiting, cutaneous hyperpigmentation), changes in mood and personality, past medical history (diabetes, thyroid disease), and laboratory test data (hyperkalemia, hyponatremia, hypoglycemia, metabolic acidosis). If undetected or left untreated, adrenocortical insufficiency is associated with significant morbidity and mortality. Acute adrenal insufficiency is the result of critical life-threatening glucocorticoid and mineralocorticoid levels [7].

MG is a rare autoimmune disease caused by autoantibodies against the nicotinic acetylcholine receptor, the muscle specific tyrosine kinase or the low-density lipoprotein receptor-related protein 4 [8, 9]. A thymoma is found in 15% of all MG patients. Thymoma–MG may be associated with neuromyotonia, Sjogren’s syndrome, or autoimmune hemolytic anemia [10]. MG is accompanied by increased risk for other autoimmune disorders [11].

Polyglandular autoimmune syndrome (PAS) includes a wide spectrum of autoimmune disorders. PAS type 1, also termed autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome, is a rare autosomal recessive disorder of childhood [12]. Conversely, PAS type 2, which is far more prevalent than PAS type 1, occurs in adulthood. Primary adrenal insufficiency is the principal presentation of PAS type 2, and it is through autoimmune thyroid diseases (e.g., Hashimoto thyroiditis, Grave’s disease) or type 1 diabetes mellitus [13]. In rare cases, PAS type 2 includes MG [14,15,16]. A coincidence of MG and Addison’s disease has been reported [4,5,6, 17]. However, the present patient only presented with primary adrenal insufficiency and MG, indicating that a diagnosis of PAS type 2 is improper (Table 2).

Table 2 Patients with association of myasthenia gravis and Addison’s disease
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Our patient had no history of other autoimmune diseases even though she presented with mild hyperkalemia (5.6 mEq/L) and mild hyponatremia (128 mEq/L). Physicians may consider these symptoms insignificant. However, we successfully diagnosed primary adrenal insufficiency due to immune adenitis early based on the presence of mild hyperkalemia, whereas in other studies, diagnoses of the condition have occurred at later stages, as indicated by the presence of severe hyponatremia (Table 2).

The three primary causes of hyperkalemia are increased K+ intake, K+ release from cells, and impaired renal K+ excretion. In our case, TTKG was low under the hyperkalemic status, indicating impaired renal K+ excretion. A differential flow chart of hyperkalemia with low renal potassium secretion is shown in Fig. 2 [18,19,20]. First, impaired renal function and ineffective plasma volume should be eliminated as possibilities. Second, body fluid status should be elevated to distinguish the low sodium (low aldosterone action) and fast chloride types (normal aldosterone action). Finally, renin, aldosterone, and cortisol levels provide additional information regarding low aldosterone production and resistance to aldosterone action.

Conclusion

Autoimmune-related adrenal insufficiency should be considered in the differential diagnosis of patients with MG who present with mild hyperkalemia. Early diagnosis of adrenal insufficiency can lead to timely steroid therapy.