pathology of the musculoskeletal system

PATHOLOGY OF THE MUSCULOSKELETAL

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Bone disorders Metabolic bone disorders

Osteoporosis (primary or secondary) Osteomalacia and rickets Paget’s disease

Genetic disorders (dysplasia): osteopetrosis, achondroplasia, osteogenesis imperfecta, hyperostosis, fibrous dysplasia.

Infectious diseases of bones - Osteomyelitis

Bone Tumors Bone injury

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Osteoporosis (primary or secondary) represents an increased loss of total bone mass due to an imbalance between bone absorption and bone formation, most often related to the aging process and decreased estrogen levels inpostmenopausal women.

Osteomalacia and rickets represent a softening of bone due to inadequate mineralization of the bone matrix caused by a deficiency of calcium or phosphate.

Paget’s disease is a disorder involving excessive bone destruction and repair, resulting in structural deformities of long bones, spine, pelvis, and cranium.Uploaded by: http://mbbshelp.com


OsteoporosisPATHOGENESIS

Osteoporosis is conventionally classified into 2 major groups:Primary osteoporosis results primarily from osteopenia without an underlying disease or medication. Primary osteoporosis is further subdivided into 2 types:

idiopathic type found in the young and juveniles and is less frequentinvolutional type seen in postmenopausal women and aging individuals and is more common.



Risk factors1. Genetic factors—more marked in whites and Asians than blacks.2. Sex—more frequent in females than in males.3. Reduced physical activity—as in old age.4. Deficiency of sex hormones—oestrogen deficiency in women as in postmenopausal osteoporosis and androgen deficiency in men.5. Combined deficiency of calcitonin and oestrogen. 6. Hyperparathyroidism.7. Deficiency of vitamin D.8. Local factors—which may stimulate osteoclastic resorptionor slow osteoblastic bone formation.



Secondary osteoporosis is attributed to a number of factors and conditions:endocrine disorders (hyperthyroidism, acromegaly, hyperparathyroidism, Cushing’s syndrome, diabetes) malabsorption disorders starvationmalignancies (multiple myeloma) alcoholism certain medications (Glucocorticoid, aluminum-containing antacids, corticosteroids and anticonvulsants antiretroviral therapy, large dose of heparin). Immobilization



Clinical features The first clinical manifestations of

osteoporosis are pain accompanied by skeletal fractures: vertebrae (compression fracture, loss of height and kyphosis), femoral neck (hip fracture), distal radius (Colles fracture)

Systemic symptoms such as weakness and weight loss.



Osteoporosis weakens the vertebrae, resulting in compression fractures of the anterior aspect of the vertebral bodies. The fractures result in back pain and, over time, shortening of stature, dorsal kyphosis, and cervical lordosis.

Loss of bone in osteoporosis is more rapid in trabecular bone than in cortical bone; hence vertebrae, because of their prominent trabecular component, are prone to fracture. Noticeable the variation in the width of the vertebrae, the fractures, and that the bone is very porous.



OsteomalaciaProduce a softening of the bones and do not involve the loss of bone matrix

Causes of osteomalacia:1. Insufficient calcium absorption from the intestine

because of a lack of dietary calcium or deficiency or resistance to the action of vitamin D (among the elderly, biliary tract or intestinal diseases, on long-term anticonvulsant, tranquilizer, sedative, muscle relaxant, or diuretic drugs, during the winter months, probably because of lessened exposure to sunlight, in cultures in which the diet is deficient in vitamin D, such as in northern China, Japan, in strict vegetarians, persons who had a gastrectomy, long-standing primary hyperparathyroidism.)

2. Phosphate deficiency caused by increased renal losses (chronic renal failure, renal tubular defects) or decreased intestinal absorption. Uploaded by: http://mbbshelp.com


Clinical features1.Bone pain, tenderness, and fractures as the disease progresses, muscle weakness2.Deformities (gravity, muscle weakness, and bone softening) - dorsal kyphosis in the spine, rib deformities, heart-shaped pelvis, marked bowing of the tibiae and femurs



This is a classic pseudofracture and is pathognomonic for osteomalacia.



Paget’s disease

Is not a true metabolic disease Localized disorder of bone remodeling,

resulting in excessive bone resorption followed by disorganized bone replacement, producing thickened but weak bone that is susceptible to deformity and fracture

Begins after age 40 years and progresses slowly over many years



Forms of involvement1.Monostotic (15%): involving one bone2.Polyostotic (85%): involving multiple bones3.Common sites include the skull, pelvis, femur, and vertebrae.Three stages of Paget disease

1.Osteolytic: osteoclastic activity predominates

2.Mixed osteolytic-osteoblastic3.Osteosclerotic: osteoblastic activity predominates “burnout stageUploaded by: http://mbbshelp.com


ETIOLOGY1. Slow-virus infection by paramyxovirus (e.g. respiratory syncytial virus, measles) in osteoclasts. However, the virus has not been cultured from the osteoclasts of Paget’s disease.2. Autosomal dominant inheritance and genetic susceptibility have been proposed on the basis of observation of 7-10 fold higher prevalence of disease in first-degree relatives.

The susceptibility gene located on chromosome 18q encodes for a member of tumour necrosis factor called RANK (receptor activator of nuclear factor). Uploaded by: http://mbbshelp.com


Clinically, the monostotic form of the disease may remain asymptomatic and the lesion is discovered incidentally or on radiologic examination.

Polyostotic form, however, is more widespread and may produce pain, fractures, skeletal deformities, and occasionally, sarcomatous transformation. Typically, there is marked elevation of serum alkaline phosphatase and normal to high serum calcium level.



In this image, the calvarium is markedly thickened by the growth of new bone. Secondly, in both specimens, the density of the bone is very heterogeneous, varying from rarefied foci to dense regions.



rat skull, especially bone brain parts, front less often. In the latter case, a characteristic look sick-lion's face



Infectious diseases of bonesOsteomyelitis

Osteomyelitis represents an acute or chronic pyogenic infection of the bone.

Inflammation of the bone marrow and other bone items

More often affects metaphysis femoral and tibial bone

Cause – staphylococci, hemolytic streptococci, Escherichia coli, Mycobacterium, pathogenic fungi.

Risk factors - endogenous microflora, acute infectious diseases, dialysis, presence of prosthetic orthopedic apparatus, etc.Uploaded by: http://mbbshelp.com


Course of disease:1.Acute osteomyelitis - sometimes lightning inflammatory diseases, trauma, iatrogenic, postradiation.2.Subacute3.Chronic forms of osteomyelitis-chronic inflammatory diseases of chronic tuberculous osteomyelitis, chronic syphilitic osteomyelitis.



HEMATOGENOUS OSTEOMYELITISIs preceded by staphylococcal or

streptococcal infections of the skin, sinuses, teeth, or middle ear→ bacteremia → Osteomyelitis

Pathogenesis - consist of bone marrow lesion appearance of serous inflammation. Serous exudate increases pressure in the closed space of bone marrow and gaversov channels → joins thrombosis of arterioles and venules bone blood flow stops (vascular insufficiency) and focal bone necrosis develops (ischemic necrosis of bone) → exudate becomes suppurative inflammation and acquires the character of phlegmon → bone marrow necrosis develops compact bone with formation of underperiosteum abscess and fistula formation



Clinical features: bacteremia - chills, fever, malaise, leukocytosis; pain on movement, loss of movement, local tenderness followed by redness and swelling.Forecast - septic form of acute hematogenous osteomyelitis causes patients to death, acute focal osteomyelitis can end with recovery. Uploaded by: http://mbbshelp.com


Chronic OsteomyelitisDevelops as a consequence of acute when the infection persists beyond 6 to 8 weeks and more.Pathogenesis and morphogenesis - formation of abscesses of bone marrow, around which the bone resorption, necrosis and sequestration of necrotic areas → a cavity containing bone sequesters. Near the hearth of inflammation of the bone thickens, deforms, fistulas are formed through which bone small sequesters. Periosteum is thickened and sclerosis. The skin is atrophic changes.Complications - pathological fractures, false joints, bleeding from the fistula, secondary amyloidosis, septicemia, tumors.Uploaded by: http://mbbshelp.com


Tuberculous osteomyelitis Occurs in 1% of cases of ТВ Extrapulmonary tuberculosis. Caused by Mycobacterium tuberculosis Bone destruction and abscess formation, caseating granulomas with extensive destruction of the bones. Local symptoms - pain, immobility, and muscle atrophy; common symptoms - swelling, mild fever, leukocytosis, night sweats, weight loss. 50% it affects the vertebrae, also is seen in the hip and knee. Common site: thoracic and lumbar vertebrae (“Pott disease”). Complications - vertebral compression fracture, psoas abscesses, secondary amyloidosis.



Osteomyelitis with vascular insufficiency

Commonly associated with chronic or ischemic foot ulcers in persons with longstanding diabetes or other chronic vascular disorders

Treatment: debridement and antibiotic - good oxygen tension in the infected site, amputation - oxygen tension is inadequate



Hematogenous osteomyelitis of the fibula of 3 months’ duration. The entire shaft has been deprived of its blood supply and has become a sequestrum (S) surrounded by new immature bone, involucrum (Iv). Pathologic fractures are present in the lower tibia and fibula.

A patient with chronic osteomyelitis of the midshaft of the tibia. A large fragment of necrotic cortex is visible deep within the draining sinus (sequestrum). The reactive periosteum has formed a collar of reactive bone (involucrum) around the chronic draining lesion. Uploaded by: http://mbbshelp.com


Classification of primary bone tumorsTissueType BenignNeoplasm Malignant Neoplasm

Bone Osteoid osteoma, Benign osteoblastoma

Osteosarcoma, Parosteal osteogenic sarcoma

Cartilage Osteochondroma, Chondroma, ChrondroblastomaChondromyxoid fibroma

Chondrosarcoma

Lipid Lipoma Liposarcoma

Fibrous and fibroosseous tissue

Fibrous dysplasia Fibrosarcoma,Malignant fibrous histiocytoma

Miscellaneous Bone marrow

Giant cell tumor Malignant giant cell, Ewing’s sarcoma, Multiple myeloma, Reticulum cell sarcoma

Diseases of the joints (arthritis)

1. Infectious arthritis2. Autoimmune3. Metabolic4. Degenerative arthritis or

arthrosis 5. Developmental disorders of the

joints6. Tumor7. Joint (Musculotendinous)

InjuriesUploaded by: http://mbbshelp.com


Degenerative joint disease

Osteoarthritis Syndrome

Osteoarthritis (OA) - formerly called degenerative joint disease, is the most prevalent form of arthritis.

Men are affected more commonly at a younger age than women, but the rate of women affected exceeds that of men by middle age.

Obesity is a risk factor for OA



Causes of Osteoarthritis1. Postinflammatory disorders (Rheumatoid arthritis, Septic

joint)2. Post-traumatic disorders (Acute fracture, Ligament or

meniscal injury, Cumulative occupational or recreational trauma)

3. Anatomic disorders (Hip dysplasia, Avascular necrosis, Paget’s disease, Slipped capital femoral epiphysis)

4. Metabolic disorders (Calcium crystal deposition, Hemochromatosis, Acromegaly, Wilson’s disease)

5. Neuropathic arthritis (Charcot joint)6. Hereditary disorders of collagen7. Idiopathic or primary variants



TYPES AND PATHOGENESISPrimary OA occurs in the elderly, more commonly in women than in men. The process begins by the end of 4th decade and then progressively and steadily increases producing clinical symptoms.

Little is known about the etiology and pathogenesis of primary OA. Genetic factors favouring susceptibility to develop OA have been observed; genetic mutations in proteins which regulate the cartilage growth have been identified e.g. FRZB gene.Uploaded by: http://mbbshelp.com


Secondary OA may appear at any age and is the result of any previous wear and tear phenomena involving the joint such as previous injury, fracture, inflammation, loose bodies and congenital dislocation of the hip. The molecular mechanism of damage to cartilage in OA appears to be the breakdown of collagen type II, probably by IL-1, TNF and nitric oxide.



PathogenesisResult from the release of cytokines such as interleukin-1 and TNF, changes synthesis protheoglicans and collagen type II → stimulate the production and release of proteases (enzymes) → destructive to joint structures → Edema of the extracellular matrix → the cartilage loses its smooth aspect → surface cracks occur allowing synovial fluid to enter and widen the crack → the vertical clefts form in the subchondral bone cartilage → fragments of cartilage to become dislodged → creating osteocartilaginous loose bodies → sclerosis, or formation of new bone (osteophyte) and cysts, usually occurs in the juxta-articular bone. Small osteophytes in the interphalangeal joints-Geberden's nodules



Clinical Manifestations- May occur suddenly- The pain worsens with use or activity and is usually

relieved by rest.- Crepitus and grinding when the joint is moved.- Joint swelling as a result of chronic inflammation in

the periarticular tissuesThe most frequently affected joints - hips, knees,

lumbar and cervical vertebrae, proximal and distal joints of the hand, the first carpometacarpal joint, and the first metatarsophalangeal joints of the feet.

- limitations of joint motion and joint instabilityUploaded by: http://mbbshelp.com


In this image, the knee joint has been opened anteriorly under the patella. For orientation, the hip is to the right and the foot to the left. There has been extensive destruction of the articular cartilage of the lower end of the femur. The synovium is not hyperplastic, nor is it inflamed. There is no evidence of pannus.



A common finding in degenerative joint disease is the formation of osteophytes at the margin of affected joints. In this image, there are three osteophytes projecting from the intervertebral joints.

Osteoarthritis of the hip is common. In this typical image, there is marked irregularity and erosion of the articular surface. Very little articular cartilage remains.



Rheumatic disorders (Autoimmune)

Rheumatic disorders are characterized by inflammation, pain, and stiffness in the musculoskeletal system.

Systemic autoimmune rheumatic diseasesSystemic autoimmune rheumatic diseases - group of chronic disorders characterized by diffuse inflammatory vascular lesions and degenerative changes in connective tissue that share clinical features and may affect many of the same organs, all of which share an autoimmune systemic pathogenesis.



Rheumatoid Arthritis Systemic inflammatory disease; 0.3%

to 1.5% of the population Women affected two to three times

more frequently than men The ages of 40 and 60 years Cause – uncertain, the disease is

initiated in a genetically predisposed individual by the activation of a T cell-mediated response to an immunologic trigger, such as a microbial agent Uploaded by: http://mbbshelp.com


Immunologic derangements1. Detection of circulating autoantibody called rheumatoid factor

(RF) against Fc portion of autologous IgG in about 80% cases of RA. RF antibodies are heterogeneous and consist of IgM and IgG class.

2. The presence of antigen-antibody complexes (IgG-RF complexes) in the circulation as well as in the synovial fluid.

3. The presence of other autoantibodies such as antinuclear factor (ANF), antibodies to collagen type II, and antibodies to cytoskeleton.

4. Antigenicity of proteoglycans of human articular cartilage.5. The presence of γ-globulin, particularly IgG and IgM, in the

synovial fluid.6. Association of RA with amyloidosis.7. Activation of cell-mediated immunity as observed by presence

of numerous inflammatory cells in the synovium



Trigger eventsThough the above hypothesis of a possible

role of autoimmunity in the etiology and pathogenesis of RA is generally widely accepted, controversy continues as regards the trigger events which initiate the destruction of articular cartilage. Various possibilities which have been suggested are as follows:

1. The existence of an infectious agent such as mycoplasma, Epstein-Barr virus (EBV), cytomegalovirus (CMV) or rubellavirus, either locally in the synovial fluid or systemic infection some time prior to the attack of RA.

2. The possible role of HLA-DR4 and HLA-DR1 in initiation of immunologic damage.



Immunopathogenesis In response to antigenic exposure (e.g. infectious

agent) in a genetically predisposed individual (HLA-DR), CD4+ T cells are activated. These cells elaborate cytokines ( tumour necrosis factor (TNF)-α, interferon (IF)-γ , interleukin (IL)-1 and IL-6). These cytokines activate endothelial cells, B lymphocytes and macrophages. Activation of B-cells releases IgM antibody against IgG (i.e. anti-IgG); this molecule is termed rheumatoid factor (RF). IgG and IgM immune complexes trigger inflammatory damage to the synovium, small blood vessels and collagen.

Activated endothelial cells express adhesion molecules which stimulate collection of inflammatory cells.

Activation of macrophages releases more cytokines which cause damage to joint tissues and vascularisation of cartilage termed pannus formation. Eventually damage and destruction of bone and cartilage are followed by fibrosis and ankylosis producing joint deformities.



Clinical manifestationsThe disease, which is characterized

by exacerbations and remissions, may involve only a few joints for brief durations, or it may be relentlessly progressive and debilitating.

- Fatigue, anorexia, weight loss, and low-grade fever - systemic manifestations

- The erythrocyte sedimentation rate (ESR) correlates with the amount of disease activity

- Anemia - associated with a low serum iron level or low iron-binding capacity is common (resistant to iron therapy)Uploaded by: http://mbbshelp.com


Joint Manifestations - symmetric and polyarticular, any diarthrodial joint can be involved (most frequently fingers, hands, wrists, knees, feet). Joint pain and stiffness that lasts 30 minutes and frequently for several hours. The limitation of joint motion (pain; later it is caused by fibrosis). Subluxation of the joints.

Extraarticular manifestations - occur in persons with the RF. Rheumatoid nodules (granulomatous lesions around small blood vessels) - tender or nontender, movable or immovable, and small or large. Vasculitis - ischemic areas - ulcerations in the lower extremities, around the malleolar areas; neuropathy; heart, lungs, and gastrointestinal tract, also may be affected. Episcleritis and scleritis, hematologic abnormalities, pulmonary disease, cardiac complications, infection, and Felty’s syndrome (i.e., leukopenia with or without splenomegaly).



This is a classic presentation of acute rheumatoid arthritis. It is polyarthritic, affects the proximal interphalangeal joints, and has produced a fusiform swelling of the soft tissue. The lesion is usually symmetrical.

In this case, there is marked destruction of the epiphyseal bone. The joint spaces are narrowed, because of the destruction of the articular cartilage. In severe cases, the joints become fused by bony ankylosis.



Metabolic diseases of the jointsCrystal-Induced Arthropathies

Crystal deposition in joints produces arthritis.

Gout Disease caused by purine disorders

Exchange and reflected increased levels of uric acid in the blood (hyperuricemia) and urine (hyperuricuria), the deposition of urates in joints, kidneys and in soft tissues.

Almost exclusively men aged 35-50 years old



The elevation of uric acid can result from:

1. Overproduction of purines,2. Decreased salvage of free purine

bases, 3. Augmented breakdown of nucleic

acids as a result of increased cell turnover

4. Decreased urinary excretion of uric acid.



Hyperuricaemia of metabolic origin

This group comprises about 10% cases of gout which are characterised by overproduction of uric acid. There is either an accelerated rate of purine biosynthesis de novo, or an increased turnover of nucleic acids. The causes of primary metabolic gout include a number of specific enzyme defects in purine metabolism which may be either of unknown cause or are inborn errors of metabolism.

The secondary metabolic gout is due to either increased purine biosynthesis or a deficiency of glucose-6- phosphatase.



Hyperuricaemia of renal origin

About 90% cases of gout are the result of reduced renal excretion of uric acid. Altered renal excretion could be due to reduced glomerular filtration of uric acid, enhanced tubular reabsorption or decreased secretion. The causes of gout of renal origin include diuretictherapy, drug-induced (e.g. aspirin, pyrazinamide, nicotinic acid, ethambutol and ethanol), adrenal insufficiency, starvation, diabetic ketosis, and disorders of parathyroid and thyroid. Renal disease per se rarely causes secondary hyperuricaemia such as in polycystic kidney disease andleads to urate nephropathy.

Reinforced exchange nucleic acids and the purine bases - myelogenous leukemia, hemoglobinорatia and psoriasisUploaded by: http://mbbshelp.com


PathogenesisHyperuricemia → monosodium urate crystals precipitate in the joint → initiate an inflammatory response → destructive changes to the cartilage and subchondral bone → repeated attacks of acute arthritis → chronic arthritis → formation of tophi urici (contain crystalline deposits of monosodium urate) in the synovium, olecranon bursa, Achilles tendon, subchondral bone, and extensor surface of the forearm → chronic tophaceous gout (degradation of subhondral departments of bones, ankilosis)



Clinical Manifestations Typical acute attack is

monoarticular (first metatarsophalangeal joint). Acute gout often begins at night and may be precipitated by excessive exercise, certain medications, foods, alcohol, or dieting. The attack may last for days or weeks. After the first attack, it may be months or years before another attack.



Gouty node (Tophus)Uploaded by: http://mbbshelp.com


PATHOLOGY OF LIGAMENT -MUSCLE APPARATUS

Depending on the etiology of the disease of muscle are divided into the following groups:

neurogenic (e.g., muscle atrophy after crossing the nerve); hereditary-muscular dystrophy (myopathy); metabolic-endocrine myopathies (such as in hyperthyroidism); toxic-myopathy caused by salts of heavy metals, alcohol, etc.; Autoimmune - myasthenia gravis, polymyositis,

dermatomyositis; infectious-viral and bacterial meningitis myositis traumatic-Lysis syndrome long muscle strength; tumor and opuholepodobnye muscle diseases.



MYASTHENIA GRAVIS

PATHOGENESIS.

The basic defect is reduction in the number of available AChRs at the postsynaptic muscle membrane. In addition, the postsynaptic folds are flattened. These changes result in decreased neuromuscular transmission leading to failure to trigger muscle action potentials and consequent weakened muscle contraction. The neuromuscular abnormalities in MG are mediated by autoimmune response.



About 85-90% patients of MG have anti-AChR-antibodies in their sera. These antibodies reduce the number of available AChRs either by blocking the active sites of the receptors or by damaging the post-synaptic muscle membrane in collaboration with complement. The exact mechanism how autoimmune response is initiated is not completely understood but the thymus appears to play a role in this process. Majority of patients of MG may have either thymoma or thymic hyperplasia; thymectomy is helpful in ameliorating the condition. The thymus possibly sensitises B cells to produce anti-AChR antibodies.



The first signs-oculomotor violations (ptosis, ophthalmoplegia, diplopia)



MYOPATHY

Myopathy or muscular dystrophy is a group of primary diseases of striated muscle, which combined a hereditary nature of suffering electoral defeat of muscle groups and progressive increasing muscle weakness.



Contrasting Features of Muscular DystrophiesType Inheritance Age at

OnsetClinical Features Other Systems Course

1. Duchenne’s type

X-linked recessive

By age 5

Symmetric weakness; initially pelvifemoral; later weakness of girdle muscles; pseudo- hypertrophy of calf muscles

Cardiomegaly; reduced intelligence

Progressive; death by age 20 due to respiratory failure

2. Becker’s type

X-linked recessive

By 2nd decade

Slow progressive weakness of girdle muscle (minor variant of Duchenne’s type)

Cardiomegaly Benign

3. Myotonic type

Autosomal dominant

Any decade

Slow progressive weakness and myotonia of eyelids, face, neck, distal limbmuscles

Cardiac conduction defects; mental impairment; cataracts; frontal baldness;gonadal atrophy

Benign

4. Facioscapulo- humeral type

Autosomal dominant

2nd-4th decade

Slowly progressive weakness of facial, scapular and humeral muscles

Hypertension Benign

5. Limb-girdle type

Autosomal recessive

Early child- hood to adult

Slowly progressive weakness of shoulder and hip girdle muscles

Cardiomyopathy

Variable progression

6. Oculo- pharyngeal type

Autosomal dominant

5th-6th decade

Slowly progressive weakness of extraocular eyelid, face and pharyngeal muscles

— Rarelyprogressive

pathology of the musculoskeletal system

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