A 38-year-old woman comes to the office with progressive muscle weakness over the last 6 months. She finds it difficult to climb stairs and comb her hair, and she is unable to walk even short distances without rest. There is no associated muscle pain. The patient was diagnosed with hypothyroidism a year ago when she started gaining weight and has been taking levothyroxine since then. Four months ago, she developed acute back pain. X-ray at that time revealed demineralization of the vertebral bones. Temperature is 37 C (98.6 F), blood pressure is 155/100 mm Hg, pulse is 76/min, and respirations are 15/min. BMI is 32 kg/m². Physical examination shows facial hirsutism and mild proximal muscle weakness in the extremities. The patient's muscles are not tender on palpation, and no fasciculations are noted. Deep tendon reflexes and sensory examination are normal. TSH is normal. Which of the following is most likely responsible for this patient's muscle weakness?

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11ec25c8_d3a0_cb82_bc81_555a1defc9e6_MD0003_00 This patient has painless muscle weakness associated with weight gain, bone loss, hypertension, and hirsutism, which is consistent with hypercortisolism (Cushing syndrome). Although it is most commonly due to exogenous administration of glucocorticoids, Cushing syndrome can also be caused by an ACTH-producing pituitary tumor (Cushing disease), ectopic ACTH production (eg, small cell lung cancer), or primary adrenal disease. This patient requires further workup (eg, urinary or salivary cortisol, plasma ACTH, adrenal or brain imaging depending on results) to determine the etiology. Regardless of etiology, myopathy in Cushing syndrome is typically characterized by weakness predominantly involving the proximal muscles and may be severe enough to interfere with daily activities. It is due to the direct catabolic effects of cortisol on skeletal muscle, which leads to muscle atrophy. Glucocorticoid-induced muscle atrophy is thought to be mediated by the inhibition of Akt-1, an intracellular signaling molecule with serine/threonine kinase activity. Interference of insulin-like growth factor 1 signaling may also contribute. Furthermore, glucocorticoids may decrease muscle cell differentiation and protein synthesis. (Choice A) Hypokalemia, hypomagnesemia, and hypercalcemia can cause muscle weakness, and hypocalcemia can cause tetany; however, none of these electrolyte abnormalities would be associated with hirsutism. In some patients with severe hypercortisolism (eg, due to ectopic ACTH syndrome), hypokalemia can develop (due to the partial mineralocorticoid effects of cortisol) and accentuate the muscle weakness; however, the weakness itself is due primarily to muscle atrophy caused by glucocorticoids. (Choice B) Mitochondria generate ATP by oxidative phosphorylation. Mitochondrial dysfunction generally involves multiple organ systems (eg, nervous system involvement, eye abnormalities, gastrointestinal manifestations). Isolated myopathy can occur but usually presents during childhood or adolescence with decreased exercise tolerance, muscle weakness, myalgias, and elevated creatine kinase. (Choices C and E) Muscle weakness in motor neuron disease (eg, amyotrophic lateral sclerosis) may be characterized by features of upper motor neuron (hyperreflexia and spasticity) or lower motor neuron (atrophy and fasciculation) dysfunction. Inflammatory myopathies can cause progressive muscle weakness that is usually associated with myalgias and muscle tenderness. These disorders would not typically cause hypertension, hirsutism, or demineralization of bone. (Choice F) Chronic inflammatory demyelinating polyradiculoneuropathy is an acquired inflammatory disorder characterized by demyelination of the peripheral nerves and nerve roots. It presents with progressive, symmetric muscle weakness and is usually associated with distal sensory loss and diminished deep tendon reflexes. Educational objective: Myopathy in Cushing syndrome is characterized by progressive painless muscle weakness predominantly involving the proximal muscles. It is due to the direct catabolic effects of cortisol on skeletal muscle, leading to muscle atrophy. References: Glucocorticoids differentially regulate degradation of MyoD and Id1 by N-terminal ubiquitination to promote muscle protein catabolism. (http://www.ncbi.nlm.nih.gov/pubmed/18296633)

A 38-Year-Old Woman Comes to the Office with Progressive Muscle