Hypothyroidism and nemaline myopathy in an adult

A significant proportion of patients with myopathy attributed to hypothyroidism remain symptomatic after long term thyroxine treatment, but muscle biopsies are rarely undertaken. Systemic review of published reports revealed only one case of typical nemaline myopathy associated with the condition. We hypothesise that hypothyroidism may not directly cause nemaline changes in muscles but it may unmask asymptomatic muscle disorders.

Case report

A 65 year old white man presented with bilateral lower limb oedema extending to the abdomen, and shortness of breath on exertion. The oedema improved on diuretics but he was noted to have muscle tenderness and weakness. He was unable to stand up from sitting. Physical examination showed proximal muscle weakness of grade 3/5. There was no previous history of an autoimmune disease and no relevant family history of muscle disease or weakness. There was no consanguinity in his family. His creatine kinase was found to be raised at 912 U/l (normal range 24 to 195 U/l) and he was referred for muscle biopsy with suspected polymyositis.

Section of muscle biopsy showed scattered atrophic fibres and occasional necrotic and regenerating fibres but no inflammation (fig 1A). Staining with ATPase showed selective fibre type 2 atrophy (fig 1B). Many fibres contained eosinophilic inclusions of varying shapes and sizes that stained dark red on a Gomori trichrome stain (fig 1C). Electron microscopy showed these bodies to either have a periodicity of 8 nm with filaments protruding from the end as from a Z disc, or to show a tetragonal filamentous array to a Z disc (fig 1D). The features were those of nemaline rod myopathy.

Figure 1 (A) HE: There is marked fibre size variation, and some fibres show ill defined inclusions. (B) ATPase, pH 9.4: section shows selective fibre type 2 atrophy. (C) Modified Gomori trichrome: there is marked variation in fibre diameter and multiple dark rod‐like inclusions are seen in many fibres. (D) Ultrastructural examination shows these inclusions to be osmophilic and approximately rectangular, the classical appearance of nemaline rods.

Following the biopsy his weight increased and he noted increasing swelling of his legs, abdomen, and chest. Settled facial features of myxoedema were noted and direct questioning revealed cold intolerance, constipation, and voice change. Thyroid function tests confirmed severe hypothyroidism. Thyroid microsomal (TPO) antibodies were strongly positive. Serum immunoelectrophoresis did not show monoclonal gammopathy and his HIV test was negative. He slowly improved on thyroid replacement but residual weakness of proximal muscle groups (grade 4/5) was still detectable by manual testing after three years of meticulous thyroid replacement. He declined a repeat muscle biopsy.

Comment

A myopathic syndrome is a common association of hypothyroidism and can be its only manifestation. Thus thyroid function tests should be always checked in people with muscle weakness. In our patient they had not been checked until after the muscle biopsy. In hypothyroidism, muscle biopsies may be normal or show non‐specific changes such as increased central nuclear counts, type 1 fibre predominance, or type 2 fibre atrophy. Common abnormalities on electron microscopy are accumulation of glycogen and lipids, abnormal mitochondria, increased numbers of mitochondria in perinuclear and subsarcolemmal regions, dilated sarcoplasmic reticulum, proliferation of T‐tubules, and focal myofibrillar degeneration. Ono et al described large irregularly shaped cores to occur in five patients with hypothyroidism, which disappeared following treatment with thyroxine.¹ They were seen in eccentric positions or in the periphery of type I fibres. They were unreactive with ATPase and PAS staining whereas with haematoxylin‐eosin and modified Gomori trichrome staining the regions were more strongly reactive than the rest of the fibre. Electron microscopy of the cores showed Z disc streaming, poorly defined myofibrils, and absent mitochondria.

Nemaline myopathy is an uncommon muscle disorder characterised by weakness and the presence of rod‐like structures inside the muscle fibres. It is clinically and genetically heterogeneous. It usually presents in childhood; adult onset nemaline myopathy is very rare. Clinical symptoms vary and many patients are symptomatic long before diagnosis. Common complaints in adulthood include weakness, especially of proximal muscles, fatigability, and myalgia. Electromyography is characteristically myopathic. Histologically it is characterised by large numbers of rod containing myofibres, numerous rods per affected myofibre, and the absence of any other specific structural abnormalities. Some of the adult onset nemaline myopathy cases described were associated with underlying immunological disorders including monoclonal gammopathy, chronic hepatitis, HIV, and HTLV‐2 infection, suggesting that an immune disturbance may play a role in the pathogenesis. Association with monoclonal gammopathy seems to bear an unfavourable prognosis.² HIV associated nemaline myopathy has distinctive pathological features on light microscopy and shows marked intrasarcoplasmic changes. Nemaline myopathy can also develop after radiation.

Our patient showed characteristic clinical and laboratory features of autoimmune hypothyroidism, and his muscle biopsy findings were characteristic of nemaline myopathy. This association has been described only once in humans, by Reyes et al in 1986. Their patient was a 50 year old black woman who presented with generalised weakness, progressive dyspnoea, and leg oedema. Examination and investigations revealed cardiac failure and hypothyroidism. Two months of thyroid replacement corrected her thyroid state but did not improve her muscle weakness. Muscle biopsy carried out that time showed abundant nemaline rods consistent with nemaline myopathy.³

Though it is possible that the abnormal histology was caused by hypothyroidism or by the autoimmune process leading to its development, we think that it is more likely that subclinical nemaline myopathy emerged during the onset of severe hypothyroidism. A recent report described three patients from three separate families who were initially diagnosed as having hypothyroid myopathy but were later found to have proximal myotonic myopathy. None of these people were symptomatic before the onset of hypothyroidism.⁴ A prospective clinical and electrodiagnostic study of adult patients with newly diagnosed thyroid dysfunction showed that 13% of them had residual muscle weakness which could be confirmed on manual muscle testing after one year of treatment.⁵ It may be that in some patients the onset of hypothyroidism unmasks a pre‐existing clinically silent or very mild myopathy.