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Myopathies Associated with Systemic Disorders and Ageing
In addition to inherited or acquired neuromuscular disorders, muscle weakness and alterations in muscle bulk can occur in association with several underlying conditions and as a consequence of ageing. Hormone imbalances, vitamin deficiencies, malignancies and ageing are the most common causes, and, although the muscle pathology is often non-specific, the pathologist should be aware of their effects.
Endocrine Disorders
Many hormones have an important role in maintaining normal muscle function. Myopathies have been described in association with several endocrine disorders, either an excess or deficiency, in particular those affecting thyroid, parathyroid, glucocorticoid, growth hormone and insulin levels. In most cases the muscle involvement is an incidental feature of the disorder, and may even be subclinical and only revealed by special investigations, such as serum enzyme levels, electromyography and biopsy, in the course of study of these disorders. In other instances, the muscle symptoms may be the presenting features and may lead to the diagnosis of the underlying disorder, e.g. thyrotoxicosis. In many cases the muscle weakness is disproportionate to the degree of muscle wasting.
There have been relatively few recent detailed histochemical or electron microscopic studies on the muscles in these various disorders, and estimation of the hormone levels is the primary diagnostic tool. Many of the reported studies from the pioneering days of muscle pathology show that, in general, only non-specific myopathic changes accompany changes in hormone levels: these relate mainly to changes in fibre size (atrophy or hypertrophy) and fibre type proportions.
Disorders of the Thyroid
Thyroid dysfunction is frequently associated with neurological manifestations ( ); several of these involve the neuromuscular system ( ).
Hyperthyroidism
There are four different muscle disorders associated with hyperthyroidism:
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thyrotoxic myopathy;
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myasthenia gravis;
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thyrotoxic periodic paralysis;
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exophthalmic ophthalmoplegia.
Thyrotoxic Myopathy
The most common myopathy in association with thyrotoxicosis is a chronic form, which may be generalized or confined mainly to proximal muscles. Although commonly seen in females, particularly after the age of 50 years, males can also be affected ( ). At times, it may precede other signs of thyrotoxicosis and in otherwise subclinical hyperthyroidism ( ). The electromyogram shows abnormality, usually of a myopathic type, in about 90% of cases of hyperthyroidism, but histological changes occur in only about 50% ( ).
The muscle biopsy may show no abnormality on light microscopy or varying degrees of fibre atrophy ( ) and fatty infiltration. Ultrastructural studies have revealed a number of relatively non-specific changes ( ). These include mitochondrial hypertrophy, focal loss of mitochondria, focal myofibrillar degeneration beginning at the Z line, focal dilatations of the transverse tubular system, subsarcolemmal glycogen deposits and papillary projections of the surface of the muscle fibres, probably resulting from fibre atrophy. Thyroid hormone influences many metabolic pathways in muscle ( ), and hyperthyroidism induces a shift in myosin heavy-chain synthesis favouring fast isoforms, which are expressed in type 2, glycolytic muscle fibres ( ), a change that is reversible after treatment and similar to what has been found in rat models. It should be noted that treatment of hyperthyroidism may result in myopathy by rapid reduction of thyroid hormone, which may induce a relative hypothyroidism (see later) ( ).
Acute thyrotoxic myopathy may involve bulbar and extraocular muscles and is probably due to associated myasthenia rather than being a separate entity.
Myasthenia Gravis
The association of myasthenia and thyrotoxicosis is well documented (see Ch. 21 ; ). The incidence of hyperthyroidism in the course of myasthenia is in the region of 5–8%, whereas that of myasthenia in the course of hyperthyroidism is much lower, being less than 0.5% ( ). The association of the two diseases is perhaps not surprising since both are recognized to have an autoimmune origin.
Thyrotoxic Periodic Paralysis
The clinical pattern of the paralytic attacks is very similar to the idiopathic type of hypokalaemic periodic paralysis. The attacks may be the presenting feature of thyrotoxicosis ( ) and usually subside after treatment of the hyperthyroidism. The condition appears to be more common in Asian races but is increasingly seen in Western countries ( ), and there is a marked preponderance of affected males.
The biopsy may show vacuolation, as in idiopathic hypokalaemic periodic paralysis, but at times may be almost normal in appearance ( ).
A mutation in the potassium channel Ki2.6 encoded by KCNJI8 has been found in up to one-third of patients with thyrotoxic periodic paralysis ( ), indicating that genetic variants in ion channels may increase the susceptibility to develop thyrotoxic periodic paralysis ( ).
Exophthalmic Ophthalmoplegia
Although usually looked upon as a complication of thyrotoxicosis, many cases do not have associated hyperthyroidism at the time of its development. Overproduction of thyroid-stimulating hormone, long-acting thyroid stimulator or a specific exophthalmos-producing factor has been invoked, but the mechanism still remains unknown ( ). suggested a delayed hypersensitivity response directed against the orbital contents as a result of the development of antibodies to thyroglobulin. Some patients may also develop a compressive optic neuropathy ( ).
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