Musculo-skeletal System

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Chapter 15 Musculo-Skeletal System

Bone Turnover

Bone is formed by osteoblasts and removed by osteoclasts.

Osteoblasts

– derived from osteoprogenitor cells.

– produce Type I collagen and other proteins.

– secrete alkaline phosphatase – a marker of bone formation.

– stimulated by mechanical stress, androgens, cytokines, e.g. TGF-β

Osteoclasts

– derived from marrow precursors.

– produce acid and enzymes to remove bone.

– produce collagen degradation products e.g. urinary HO proline – a marker of bone destruction.

– stimulated by cytokines e.g. IL-1, IL-6 (indirectly by PTH).

– inhibited by oestrogens.

The activities of the two cell types are closely ‘coupled’ in the normal process of bone turnover. In the adult 10% of the skeleton is replaced annually. The process has activating and inhibitory arms.

Activation

Osteoblasts bear RANKL (Receptor Activator of NF-κB Ligand)

Inhibition

Under other circumstances osteoblasts and other cells produce osteoprotegerin (OPG) a soluble molecule which blocks activation through RANK.

Osteoporosis

OSTEOPOROSIS is the commonest disorder of bone. It is defined as a systemic disease characterised by:

(1) low bone mass.

(2) microarchitectural deterioration of bone, with

(3) an increase in bone fragility and susceptibility to fracture.

A patient is said to have osteoporosis if bone mineral density >2.5 standard deviations below the mean of normal young subjects.

Clinical effects: – osteoporosis is a disease predominantly of post-menopausal females, but men are also affected.

1. It causes bone fractures (collapse) of vertebral bodies with loss of height and kyphosis.

2. Fracture of neck of femur or other long bones (especially Colles’ fracture of distal radius).

Note: In osteoporosis, the routine serum biochemical tests – particularly the calcium levels – are within the normal range.

Pathology: The changes in the vertebral bodies are shown.

Note:

(i) The bone has a normal calcium content.

(ii) Bone loss is most marked in cancellous bone with its high turnover, but cortical bone is also affected.

Aetiology

In normal bone the dynamic processes of formation and resorption are in balance.

In osteoporosis the balance is upset by

(1) diminished formation

(2) increased resorption, or both

Bone mass decreases with age in both sexes: in old age, osteoblastic activity falls.

PEAK BONE MASS is important – a high initial figure makes osteoporosis less likely. This depends on factors including:

(a) Genetic predisposition – polymorphisms of Type I collagen gene and other genes regulating bone cell activity.

(b) Nutrition – especially calcium intake.

The aetiology can be summarised as follows:

Localised osteoporosis is commonly due to disuse and is seen as a complication of other disorders, e.g. local immobilisation following fracture; limb paralysis and adjacent to severe joint disease with limitation of movement.

Osteomalacia and Rickets

Osteomalacia and rickets are disorders of bone due to failure of mineralisation of newly formed osteoid, caused by vitamin D deficiency in almost all cases. The poorly calcified bones are soft causing deformity or fracture.

Osteomalacia occurs in adult life and affects the osteoid which is being continually laid down in the normal remodelling of bone.

Rickets affects the growing child. As well as deformity and fractures, there is disturbance of growth plates. X-ray may show linear partial fractures of long bones which have failed to calcify (Looser’s zones).

The following simplified diagrams indicate the causes of vitamin D deficiency and its effects on bone.

Causes of deficiency:

Effects on Bone

Note: The hypocalcaemia seen in osteomalacia stimulates an increase in PTH levels and mild hyperparathyroidism.

Metabolic Bone Disease

In rickets the growing ends of long bones are abnormal.

This results in stunting of growth and bowing of the lower limbs.

In females permanent deformities of the pelvis can cause serious difficulty during childbirth.

Enlargement of costochondral junctions gives the so-called rickety rosary

Hyperparathyroidism (see P.642)

Bone changes may be seen in hyperparathyroidism, especially when severe or long-standing. There is increased bone resorption due to PTH-induced osteoclastic activity. Due to ‘coupling’, osteoblastic activity is also increased but the net effect is bone loss.

These changes affect all bones. There may be marked loss of bone with numerous osteoclasts and haemosidern pigment – the so-called ‘brown tumour of hyperparathyroidism’, which can mimic giant cell tumour.

Renal Osteodystrophy

Bone disease is common in chronic renal failure. It is a combination of osteomalacia and hyperparathyroidism, together with loss of bone synthesis.

Paget’s Disease of Bone

This disease of unknown aetiology usually presents after the age of 50 years and is more common in males. It is fairly common (3% of autopsies), but only in its more severe forms are there clinical symptoms. The disorder is focal: the bones particularly affected are the pelvis, vertebrae, skull and lower limbs. It has been suggested that virus infection (e.g. measles, distemper) of osteoclasts is responsible. Genetic factors are important.

To begin with, there is a localised increase in osteoclastic activity causing bone resorption; soon there is a marked osteoblastic reaction with bone resorption and deposition proceeding chaotically, so that irregular bone trabeculae with mosaic cement lines are formed. The bone may be thickened, but its structure is defective and weak. Biochemical changes reflect the cellular activity at trabecular level: Alkaline phosphatase ↑(osteoblastic); urinary hydroxyproline ↑(collagen destruction).

Often asymptomatic, the main effects are:

• Bone pain and deformity

• Pathological fracture

• Osteoarthritis (due to abnormal stresses caused by bone deformity)

• Nerve compression leading to deafness or spinal cord compression

• An increased risk (×30) of the development of bone sarcoma.

The use of bisphosphonates offers effective therapy in many cases.

Bone – Miscellaneous

Osteonecrosis (Avascular Necrosis)

Interruption of its blood supply causes bone to undergo necrosis. This tends to occur with fractures at sites where the vascular supply is damaged. Fractures of the femoral neck and scaphoid bone are good examples.

Non traumatic causes include corticosteroid therapy, alcoholism, sickle cell anaemia, Gaucher’s disease and historically in decompression in those working in increased atmospheric pressure (caisson disease).

Bone necrosis occuring at an articular surface often leads to degenerative arthritis.

Note: These areas of necrotic bone may appear radiodense due to disuse osteoporosis of the adjacent living bone.

In children and adolescents osteonecrosis occurs at several epiphyseal sites probably due to trauma). The commonest is Perthes’ disease in which necrosis of one or both femoral heads occurs in children aged 4–10 years (male: female = 5:1).

Fibrous Dysplasia of Bone

This disorder may affect one (monostotic) or several (polyostotic) bones. On histology, well demarcated fibrous tissue containing small abnormal woven bone trabeculae is seen. Somatic mutations of the GNAS1 gene which encodes the α subunit of a stimulatory G-protein are responsible. Whether the disease is polyostotic or monostotic depends on the stage of development of the embryo when the mutation occurs, a state known as mosaicism.

Complications

Fracture or deformity of the weakened bone.

Infections of Bone

Acute Osteomyelitis

Classically caused by Staphylococcus aureus. This affects the metaphyses of long bones in children. Nowadays the incidence has been greatly reduced and the use of antibiotics aborts the development of the disease. The bacteria are blood borne and settle in the cancellous bone of the metaphysis. The effects are dramatic and rapidly progressive.

The presence of necrotic bone ensures that the inflammation continues.

The late complications are chronic osteomyelitis, disturbance of bone growth, amyloid disease may occur and occasionally squamous carcinoma arises in a sinus.

Other pyogenic bacteria can cause osteitis – the salmonella group (esp. S. typhi) and brucella, the latter often causing a low grade osteitis of the spine.

With inadequate antibiotic treatment, acute inflammatory processes may be converted into low grade osteitis. Staphylococcal infection of the spine may present in adults in this way.

Tuberculosis

The incidence of bone and joint infection parallels that of the more common pulmonary infection. It is therefore low in developed countries but still significant elsewhere, and has risen in association with HIV infection.

The spine and growing ends of long bones including the epiphyses are affected by blood borne spread and the infection spreads to the adjacent joints.

Bone is destroyed and replaced by granulomatous inflammation with caseous necrosis. Spinal infection spreads into adjacent tissues and leads to ‘cold abscess’ formation.

Although the progress is much less rapid than in acute osteomyelitis, without adequate treatment serious damage to bones and joints occurs.

Developmental Abnormalities

Generalised abnormalities are rare and usually inherited.

1. ACHONDROPLASIA is the commonest cause of dwarfism, with short, deformed limbs and a waddling gait. The bones at the skull base are underdeveloped.

A mutation of the fibroblast growth factor receptor gene (FGFR3) is responsible, which causes constitutive activation and inhibits cartilage growth. Although inherited as an autosomal dominant trait, 80% of cases result from new mutations.

2. In OSTEOGENESIS IMPERFECTA (Brittle bone disease) the thin brittle bones fracture easily and a history of multiple fractures with minimal cause is the usual presentation. It is important to distinguish this from ‘non-accidental injury’.

The basic defect is in the osteoblasts which fail to synthesise collagen properly, due to mutations affecting the Type I collagen genes on chromosomes 7 and 17. The severity of the disorder depends on the type of mutation, some cases being lethal in utero.

Patients may have:

(a) very thin sclerae which appear blue

(b) abnormal tooth development due to defective dentine formation.

3. OSTEOPETROSIS (Marble bone disease of Albers–Schönberg) is a disorder in which osteoclasts are absent or defective. This results in failure of bone remodelling and abnormal conversion of cartilage to bone. The whole skeleton becomes dense and the bones thickened, but weakened.

Complications are:

(a) anaemia due to failure of development of the bone marrow cavity

(b) fractures

Bone marrow transplantation provides functioning osteoclasts and reverses the skeletal abnormalities.

Cysts of Bone

Simple bone cysts (unicameral-single chamber) have a thin fibrous lining and occur in the proximal humeral and femoral metaphyses of children. They often present with fracture.

Aneurysmal bone cysts (expanding blood-filled cysts in adolescents) are eccentric expanding blood-filled cysts presenting with swelling, pain or fracture.

These true cysts should not be confused with lytic lesions which appear cystic on X-ray.

Tumours in Bone

Primary bone tumours are rare. There are both benign and malignant forms, examples of which follow. In contrast, metastatic tumours and myeloma are common.

Osteoid Osteoma

This uncommon benign tumour has a striking clinical presentation and a distinctive pathology.

Clinical: Classically, an adolescent complains of well localised, increasingly severe bone pain. Aspirin and non steroidals give relief.

Pathological: The essential lesion is a small focus (nidus) of newly formed irregular trabeculae of osteoid or poorly calcified woven bone in a highly vascular stroma.

Note: Reaction in surrounding bone; sclerosis of adjacent cortex and periosteal bone thickening.

Giant Cell Tumour (Osteoclastoma)

This uncommon tumour presents in adult life (age 20–40 years), at the end of a long bone, especially adjacent to the knee. The tumour destroys bone and the cortex gradually expands, becoming egg-shell thin. Pathological fracture is common.

The histology is characteristic:

Behaviour: Almost all giant cell tumours are benign. Most are cured by thorough removal: approximately 20% recur: well under 5% become malignant and metastasise to the lungs.

EOSINOPHILIC GRANULOMA (at the benign end of the spectrum of Langerhans histiocytosis) usually presents as single osteolytic radiolucent lesions of bone in children. Vertebral collapse and pathological fractures are sometimes seen.

The prognosis is usually good.

The histological appearances are typical.

Malignant Tumours

Primary malignant tumours of bone are not common, but they are important as many arise in young people and are highly malignant. Some arise in older people with pre-existing bone disorders, e.g. Paget’s disease, previous irradiation.

Osteosarcoma

This highly malignant tumour is the commonest primary malignant tumour of bone. It affects two distinct age groups and there is a preponderance of males over females.

Young age group – majority of cases (10–25 years)	Elderly subjects (over 60 yrs.)
The tumour usually arises near the end of a limb long bone (particularly around the knee).	In 50% of this group, Paget’s disease is associated. Long bones, vertebrae and pelvis are often affected, and tumours may be multicentric in origin.

The ‘classic’ tumour in an adolescent begins in the metaphysis of the medullary cavity. Most patients complain of bone pain and when the tumour penetrates the cortex there may be a soft-tissue swelling.

Note: At this stage lung metastases may be present.

Histologically, varying amounts of osteoid, woven bone and sometimes islands of primitive cartilage are seen. The tumour cells are pleomorphic and mitotically active. With modern chemotherapy 50–60% of patients survive for 5 years.

Chondrosarcoma

This shows a much slower growth pattern and affects the age group 40–70 years. Multiple enchondromatosis pre-exists in a small number of cases. The tumours arise particularly in the limb girdles and proximal long bones and consist of lobules of cartilage. Progressive local extension is usual. Metastases, usually to the lung, are rare.

Ewing’s Sarcoma

This rare malignant tumour affects the young (age 5–20 years) and arises in long bones, pelvis, ribs and scapulae. It is very aggressive, metastasising early to lungs and other bones.

The tumour cells are small and uniform. Fever and an elevated white count are common and may mimic osteomyelitis. The histological appearances may mimic lymphoma.

Ewing’s sarcoma is a primitive neuro-ectodermal tumour associated with translocation and fusion of genes, typically the EWS and Fli-1 genes, on chromosomes 11 and 22. With chemotherapy, survival is similar to that of osteosarcoma.

Lymphoid Tumours

Lymphoma and myeloma (see p.435) may arise in bone, causing bone destruction.

Secondary Tumours in Bone

this is by far the most common type of tumour in bone.

Tumours which show a predilection for spread to bone are carcinoma of the prostate, breast, lung, kidney and thyroid. Metastases are usually multiple. The incidence of bone secondaries especially in the spine is very high when these tumours become widespread. Occasionally latent renal and thyroid cancers present as a single bony metastasis with pathological fracture.

Metastases are usually osteolytic with extensive destruction of bone. In a minority of cases, osteoblastic activity is stimulated by the presence of the tumour so that dense reactive bone is formed. Osteosclerotic secondaries of this type are seen particularly in cancers of the prostate and breast.

Joint Diseases

The diagram illustrates the structure of a synovial joint.

The two most common joint diseases illustrate how individual components of a joint may be initially affected:

As the diseases progress, other secondary effects are added and may obscure the basic pathology.

Joint Trauma

Trauma is very variable in its severity and effects.

At one end of the scale a single incident of ‘sprain’ or ‘strain’ involves only minor soft tissue damage with minimal associated haemorrhage – in these circumstances the healing capacity of joints is rapid and complete.

With mild degrees of trauma, particularly if repeated, the synovial membrane shows nonspecific reactive changes which include hyperaemia and a mild chronic inflammatory cellular infiltrate. There is often a joint effusion.

Serious damage to joints include:

Possible sequels are:

1. The articular surface is permanently deformed (ineffective repair of cartilage).

2. Loose body continues to cause traumatic damage to cartilage.

3. Ligaments may not heal or are united by poor scar tissue.

The medial meniscus of the knee is susceptible to tears:

Locking of the joint and effusion are common.

Apart from damage directly attributable to trauma, the most important consequence is an increased risk of osteoarthritis.

Osteoarthritis (OA)

This is the commonest disorder of joints and, by causing pain and stiffness, is the commonest cause of chronic disability after middle age. The basic pathology is degenerative and is similar to the changes of ageing.

The disorder is divided into two main groups. In both types of osteoarthritis the basic pathological processes are the same.

1. In secondary OA there is a clear association with some predisposing condition which may be virtually any abnormality of a joint. Of particular importance are:

a) abnormality of the articular surfaces (e.g. following injury).

b) abnormal stresses on the joint (e.g. the increased weight-bearing demanded by obesity; association with particular occupations and sports), or abnormal alignments.

c) previous inflammation e.g. rheumatoid arthritis, sepsis.

2. In primary OA no obvious predisposing cause is evident, but often runs in families. In some, mutation of Type II collagen gene is found.

The integrity of the articular cartilage represents a balance between ‘wear and tear’ losses and replacement by chondrocytes of the specialised matrix.

The earliest change in ageing and OA is in the chemical composition of the matrix which becomes softer. This is followed by progressive characteristic morphological changes.

The synovial membrane may show mild, non-specific inflammation and effusion may occur but these changes are secondary.

Distribution: secondary OA often affects a single predisposed joint.

In primary OA, the larger weight bearing joints and the spine in particular are susceptible, but interphalangeal joints bear osteophytic outgrowths (Heberden’s and Bouchard’s nodes). Osteoarthritis is the main indication for hip and knee replacement surgery.

A particularly severe form (Charcot’s joint) is seen when the nerve supply to a joint is defective – neuropathic arthropathy.

Gout

Patients with gout develop acute arthritis often of the great toe. Uric acid is produced in purine (DNA) breakdown. In gout, there is hyperuricaemia (serum uric acid >7 mg/dl). Periodically, urate crystals are deposited within the affected joint, at first in the articular cartilage, but chronically in the adjacent bone and soft tissues forming masses known as tophi. Joint aspiration shows characteristic appearances.

PSEUDO-GOUT. In this condition of the elderly, rhomboid crystals of calcium pyrophosphate are deposited in the joint, evoking a similar inflammatory reaction. Larger joints such as the knee tend to be affected; chronic degenerative arthritis often supervenes or co-exists. The radiological appearances are known as chondrocalcinosis.

Rheumatoid Arthritis (RA)

Rheumatoid arthritis (RA) is a common systemic disease (1–3% of population in Europe). The most affected tissue is the synovial membrane. The typical clinical course is insidious in its onset and progression; in a minority, the onset is acute and the progress rapid. Frequently there are remissions and exacerbations.

Incidence: female > male 3:1

Age of onset: usually 35–55 years, but also in childhood – usually severe.

Typically, affecting multiple joints symmetrically, the joints of the hands and feet and the knee joints are affected; there may be involvement of the spine.

Pathology: The synovial membrane shows chronic inflammation.

Sero-Negative Arthritis

Ankylosing spondylitis (AS) is an arthritis affecting particularly the sacroiliac, costovertebral and vertebral joints, but peripheral arthritis is also seen.

Incidence: 0.05% of population male:female; 3:1.

Age of onset: Young adults progressing into middle age.
Rheumatoid factor negative.

The disorder is, like RA, an active chronic arthritis, but differs in that it may cause osseous ankylosis (bony union), so that no movement of the affected joints is possible.

Aortitis leading to aortic incompetence and uveitis may be seen.

Psoriatic arthritis affects the axial and peripheral joints. Typically the distal interphalangeal joints are involved and the adjacent nails are affected.

Reiter’s syndrome: This is a syndrome of polyarthritis, urethritis and uveitis following infections, e.g. chlamydia, yersinia and salmonella. The detailed mechanisms are unclear.

HLA association. Ankylosing spondylitis, psoriatic arthritis and Reiter’s syndrome are associated with HLA-B27 (>95% in AS). Genetic susceptibility is an important factor predisposing to the arthritis.

No such association with HLA-B27 is evident with RA, which however shows an association with HLA-DR4, twice that of the general population.

	OSTEOARTHRITIS	RHEUMATOID ARTHRITIS
Type of disorder	Degenerative	Inflammatory
Site of initial damage	Articular cartilage	Synovial membrane
Age	Late middle age +	3rd decade (any age)
Joints affected	Large weight bearing often single, pre-existing local factors in some cases	Small joints of hands and feet, multiple
Systemic disease	None ESR – normal Rheumatoid factor – absent	++ ESR ↑ Rheumatoid factor positive Secondary anaemia

Infections of Joints

1. Acute infective arthritis

(a) Primary pyogenic haematogenous infection is now rare. It remains, however, a serious complication in joints already damaged. S. aureus is the common infecting organism.

The essential changes are:

(b) Arthritis complicating gonorrhoea and brucellosis.

In both of these conditions, a polyarthritis may occur in the acute phase and, in a small number, continues as a low grade arthritis. The spine particularly is affected in brucellosis.

2. Tuberculous arthritis

In Western countries the incidence is low: a few cases arise complicating reactivated pulmonary tuberculosis in the elderly. If untreated, there is a low grade chronic inflammation with effusion and progressive destruction of tissues.

The diagnosis requires culture of joint fluid and/or biopsy when the typical histology of tuberculosis is seen.

3. Lyme disease is a polyarthritis due to Borrelia burgdorferi transmitted by bites from deer ticks.

Joint and Soft Tissues – Miscellaneous

Pigmented Villonodular Synovitis (PVNS) (Tenosynovial Giant Cell Tumour)

This may affect any synovial tissue, but the knee and hip joints are most commonly involved.

There is a strong male predominance (age 20–50). The synovial membrane shows proliferation of brown pigmented large villi or rounded nodules.

It is now thought to be neoplastic but to all intents it never metastasises.

The so-called benign giant cell tumour of tendon sheath is now considered to be a solitary variant of PVNS.

Soft Tissue Tumours

These are dealt with on pages 123 and 124: 128–130.

Loose Bodies in Joints

Loose bodies are usually found in diseased or damaged joints and their presence tends to aggravate any existing disease. Clinically, there is often recurrent ‘locking’ of the joint.

Para-Articular Tissues – Miscellaneous

Bursae

These are synovial-lined spaces usually overlying bony prominences, e.g. the olecranon and patella, and often connected with adjacent joint spaces. They may become inflamed (bursitis).

Ganglion

This is a swelling which forms in relation to joint synovium or more usually, tendon sheath due to myxoid degeneration. It is not lined by synovium. Ganglia are classically seen around the wrist.

This type of myxoid cystic degeneration may occur at other less prominent sites, e.g. within the cartilagenous menisci of the knee.

Dupuytren’s Contracture. See page 124.

Collagen Diseases

This term describes a group of multisystem diseases, many autoimmune in origin.

The group includes rheumatoid arthritis (RA); systemic lupus erythematosus (SLE); systemic sclerosis; polyarteritis nodosa (PAN) and dermatomyositis.

Systemic Sclerosis (Scleroderma)

This is a rare, slowly progressive disease in which there is gradual fibrosis of various organs including the skin (face and hands), gastrointestinal tract, heart and lungs. It is associated with Raynaud’s disease. The basic abnormality is in the small blood vessels, which show sclerosis with intimal thickening. The change is associated with fibrosis of the surrounding tissues. Auto-antibodies, typically against nuclear components, are often found.

In collagen diseases, the basic mechanisms are inflammatory and are mediated by autoimmune processes. The inflammatory damage is very variable in its severity, its site of predilection and even its local effects. Multiple factors, of which inherited susceptibility and resistance are important, are involved. The following diagram illustrates the basic mechanisms.

Skeletal Muscle

Muscle Contraction

The basic mechanism is as follows:

There are 3 types of muscle fibre, related to differences in functional activity.

Note: Most muscles are a mixture of the 3 fibre types, but the proportion varies according to the function of the muscle.

In section, the three fibre types are identified by their ATPase activity.

It is of interest that the muscle fibre function is not intrinsic but is conditioned by its type of nerve supply: any single anterior horn cell innervates fibres of only one type.

Muscle Innervation

The motor unit consists of: a single lower motor neurone (LMN) — and the muscle fibres it supplies.

Muscle Spindles

Muscle spindles are bundles of specialised fibres which control and refine muscle contraction and are important for proprioception. They are separately innervated from the surrounding fibres.

Atrophy And Hypertrophy

Generalised disuse atrophy occurs as a result of prolonged immobilisation in bed. Local atrophy follows immobilisation due to joint disease or after bone fractures.

Hypertrophy of muscle tissue in response to increased work load is well seen in athletes.

Note: Atrophy may be partially masked by increased fat in the septal tissues.

Neurogenic Atrophy

This form of atrophy is seen when the nerve supply is damaged. The distribution of nerve fibres within the muscle is important and is represented diagrammatically in respect of two motor units: A and B.

Note that while A and B respectively innervate the majority of fibres in bundles A′ and B′, there is overlap between bundles. Since many axons supply a muscle the overlap is considerable.

Apart from complete traumatic section of a peripheral nerve, it is unusual for all motor fibres to a muscle to be destroyed. Both the basic pattern of innervation and the variations in nerve fibre damage are reflected in the histological appearances in the denervated muscle.

1. Pattern of atrophy

2. Re-innervation

In an area of denervation, the terminal axonal branches of intact neurones sprout and can re-innervate the atrophic fibres. The effects of denervation and re-innervation are shown in a muscle bundle supplied by 2 axons A and B.

Myasthenia Gravis

The motor end–plate is the specialised neuromuscular junction situated at the middle of each muscle fibre. The nervous impulse causes release of acetylcholine at the specialised nerve endings – depolarisation at this site is the stimulus to contraction. The sarcolemma at this site contains cholinesterase.

In myasthenia gravis young females are most affected with muscle weakness and early fatigue of the ocular and head and neck muscles particularly.

Antibodies to acetylcholine receptors are present in 90% of cases, blocking the effect of acetylcholine at the motor end plate.

There is a strong association with thymic abnormalities. In young women this is usually thymic germinal centre hyperplasia: in middle aged males a thymoma may be present.

Muscle Damage

(a) Trauma and ischaemia

Trauma and ischaemia may combine to cause necrosis of a mass of muscle and the effects may be serious.

The latter situation is well exemplified in the CRUSH SYNDROME – classically seen in building collapse.

Muscular Dystrophy

Muscular dystrophies are inherited diseases, causing muscle damage and weakness.

Duchenne Muscular Dystrophy

This is the commonest and most serious form.

Clinical features: Muscle weakness in early childhood; typically wheelchair-bound by 12 years of age and death by late teens or early twenties.

Pathology: The main features are

(1) muscle fibre necrosis and

(2) regeneration.

In time, fibres are atrophic and there is fibrosis and fatty replacement.

Biopsy shows:

Aetiology: This is an X-linked recessive disease occurring almost exclusively in boys. The dystrophin gene lies on the short arm of chromosome X.

Biopsy in early stages shows a lack of dystrophin using immuno-staining (anti-dystrophin antibodies).

Genetic screening for mutations of the dystrophin gene is now available.

Becker type muscular dystrophy is a milder form caused by mutation in the dystrophin gene resulting in diminished levels of the protein.

Other muscular dystrophies include the facio-scapulohumoral, limb girdle and myotonic dystrophy forms.

Inherited Myopathies

Specific Metabolic Defects

There is a group of genetic myopathies with specific biochemical or morphological abnormalities.

In some, the inborn error of metabolism is generalised and includes muscle; in others it is confined to the muscle fibre. Some examples will be given:

(1) Glycogen storage	(2) Lipid metabolism	(3) Periodic paralysis
Type 2 (Pompe) – deficiency of acid maltase Type 5 (McArdle) – muscle phosphorylase Type 7 – phosphofructokinase (PFK)	Defect in free fatty acid transport into and utilisation within fibre. (a) carnitine palmityl transferase (CPT) (b) muscle carnitine deficiency

Associated with hypo-and hyperkalaemia – the muscle defect is a vacuolar degeneration of the sarcolemma (4) Morphological abnormalities (a) Mitochondrial (b) Others Large or increased numbers of mitochondria – abnormal oxidative processes (i) Central core myopathy