Pathology lecture 6

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Muscle diseases

muscle type I (red) slow twitch muscle fibbers (numerous

mitochondria and much more of myoglobin); more enzymes for Krebs cycle (aerobic oxidation) than in fast twitch; almost unstained for alkaline ATPaze reaction

type II (white) fast twitch muscle fibbers; faster stronger contraction; Embden-Meyerhof pathway of glycolysis (anaerobic); androgenic steroids cause their hypertrophy, and disuse results in their selective atrophy

In humans no muscle composed exclusively of one

fibber type, but proportions vary from muscle to muscle and from person to person (genetically determined).

Muscular dystrophy disease characterised by progressive weakness of the

voluntary muscle caused by primary muscle degeneration or by nervous

system involvement primary muscular degeneration hereditary/familial;

relentlessly progressive morphology: degeneration of muscle fibers regenerative activity progressive fibrosis infiltration of the muscle with fatty tissue no inflammation

Duchenne Muscular Dystrophy (1)

(proressive muscular dystrophy//DMD) non-inflammatory myopathy severe, progressive and fatal, appears before the age of

4 inherited, X-linked, DMD and Becker muscular dystrophy

(BMD) occurs in 1/3,500 males (almost like cystic fibrosis)

the Duchenne-Becker gene (one of the largest known human genes 2x106 base pairs) located on the chromosome X

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boys suffer from progressive degeneration of muscles (mainly the pelvic and shoulder girdles)

caused by deficiency of dystrophin (a cytoskeleton protein located on the cytoplasmic face of the plasma membrane, which linked to by an integral membrane protein; play role in mechanical properties and flexibility during contraction and relaxation)

DMD - no dystrophin BMD - smaller then normal amount of dystrophin DMD - 33% new mutations 33% mutations in mother 33% family disease (more then one generation)


pathology: relentless degeneration prolonged efforts to repair and regeneration progressive fibrosis progressively decreasing number of muscle fibers + fibro-fatty connective tissue

early development of endomysial fibrosis


clinical diagnosis elevelated of creatine kinase levels in the blood +

muscle biopsy (morphologica changes observed even in utero)

prenatal diagnosis (DNA analysis and/or elevated serum creatine kinase levels found in up to 75% of carrier mothers)


clinical features: normal growth within 1 year of life by the age of 18

months 50% of patients fail to walk proximal muscle weakness and pseudohypertrophy of the calf muscles

striking tendency to form contractures when immobilized for short time period

more then 90% affected boys are chair-bound by the age of 11 years

patients are bedridden by the age of 15 decreased intelligence (20% are significantly retarded) death occurs at the mean age of 17 years respiratory

inssuficiency and cardiac arrythmia

Becker Muscular Dystrophy

milder form of DMD later onset at the age of 12, all patients are still walking 95% survive beyond the age of 21

Myotonic Dystrophy (1)

the most common form of adult muscle dystrophia sustained muscle contraction and rigitity (myotonia) +

progressive muscular weakness and wasting incidence 14/100,000 gene responsible for the disease 19q13.3 (novel

cyclic AMP-depended protein kinase excitability of sarcolemma becouse of abnormal forsorylation of ion channels) in most cases descenceded from one original mutaion

aticipation aerlier age of onset and increasing severity of symptoms in successive generations unstable genomic segment (CCG repeats)

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pathology: highly variable changes even in one patient atrophy of type I fibers with hypertrophy of type II fibers internally situated nuclei ring fibers in ATPase reaction necrosis and regeneration are not prominent


clinic: three types:

congenital only in offspring of women who themselves exhibit symptoms of myotonic dystrophy newborns with muscle weakness but myotonia is inconspicious or absent (appears

later) mental retardation

classic adult onset muscle weakness and stiffness principally in the distal limbs facial and jaw muscles always affected (severe ptosis) additionally cataracts and personality deterioration some patients have smoth muscle involvement (GI, gallbladder, uterus, arrthmias)

minimal symptoms with late onset

CONGENITAL MYOPATHIES

abnormalities confined to type I fibers type I fibers predominance (better to say: failure of type II fibers to

develop) muscles do not show active degeneration no serum creatine kinase

elevation


Central core disease congenital hypotonia + proximal muscle weakness decreased deep tendom reflexes delayed motor development sporadid or AR or AD muscle strenght never becoms normal pathology: predominance of type I fibers central zone degeneration (loss of membranous organelles with or without

disorganization of myofibrillar architecture) [like in active denervating conditions; but no evidence of such process]

periphery is unremarkable


Rod (Nemaline) myopathy tangled/threadlike mass inclusions within muscle fibers rod-shaped structures group of diseases:

congenital (hypotonia, deleyed motor milestones, variable sevirity + kyphoscoliosis; in some involvement of face, pharynx, and neck)

later-onset (childhood and adult; some muscle degeneration + elevation of creatine kinase)

pathology: predominance of type I fibers rod-shaped structures (inclusions arising from Z line)


Central nuclear myopathy (myotubular myopathy) group of diseases AR, AD, X-linked in severe cases death in neanatal period becouse of respiratory

insufficiency

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INFLAMMATORY MYOPATHIES

a. dermatomyositis b. polymyositis c. inclusion body myositis Pathogenesis: autoimmune origin: follow viral infections detected autoantibodies muscle cell injury causwed by cytotoxic lymphocytes or complement-

mediated microangiopathy


dermatomyosistis: lymphoid infiltration (mainly B cells) high ratio of CD4+/CD8+ cells proximity of helper T cells to B cells and macrophages paucity of lymphocytes in uninvolved muscle fibers injury produced primarly by complement-mediated cytotoxic antibodies

direct against the microvasculature of skeletal muscle tissue ischemia of individual muscle fibers, microinfarcts, and secondary

inflammation


polymyosistis and inclusion body myosistis direct muscle damage by cytotoxic T cells no microangiopathy healthy muscle fibbers surrounded by T cell (CD8+) and macrophages

degeneration of muscle fibber (express MHC-I Ag on sarcolemma)

MIASTENIA GRAVIS

Myasthenia gravis (2)

Autoimmune disease blockage and destruction of acetylcholine receptors (AChR) of motor end plate by autoantibodies (IgG, may cross the placenta).

Additionally, anti-AChR antibodies fix complement and lead to direct injury to the postsynaptic membrane.


MORPHOLOGY: no specific abnormalities on gross examination or LM Sometimes focal collections of lymphocytes

(lymphorrhages). In severe cases sometimes diffuse changes with type 2 fiber

atrophy. Immunohistochemistry: IgG and complement components

on the motor end plate. Electron microscope: damage of the motor end plate with

the loss of the normally complex folds.

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CLINICAL FEATURES: muscle weakness that is aggravated by repeated

contraction muscles with the smallest motor units are affected first, most

typically ocular muscles (bilateral ptosis, diplopia) - only ocular problems in 20% of patients.

In others, diasease progresses: facial muscles, limb girdle muscles, and respiratory muscles.

Progression usually slow, respiratory muscles involvement 5-20 years after the onset.

Sensory and autonomic functions NOT affected. Untreated, 40% of patients will die within 10 years.

Myasthenia gravis (6) TREATMENT: anticholinesterases. in crisis situations (i.e. when respiratory function is

compromised) high-dosage corticosteroids, plasma exchange.

Thymectomy is indicated remmision in many patients, esp. in young women with recent onset of MG and thymic hyperplasia.

Inherited and developmental diseases

Osteogenesis imperfecta Osteopetrosis Cleidocranial dysplasia (dysostosis) Achondroplasia Fibroosseus diseases Cherubism

Osteogenesis imperfecta brittle bone disease hereditary disease (heterogeneous group) defective collagen type I synthesis (lower amount of procollagen OI type I)

deletions and mutations of collagen type I gene OI type II, III, and IV

characterized by generalized osteoporosis with slender bones ( tendency for pathologic fractures; they heal sometimes exuberant callus formation)

the long bones have narrow and poorly formed cortices composed by immature, woven bone

Osteogenesis imperfecta symptoms when child learns to walk fragile as a china doll thin, bulging skull and blue sclera, defness (mulitiple farctures) hypermobile joints and thin translucent skin and heart valve defects associated with dentinogenesis imperfecta (mainly deciduous

dentition) in OI type I because of hypolpalsia of the dentine and pulp, the teeth

are misshapen and bluish yellow four types:

type I most common (blue sclera, bone fragility and deafness) type II most severe (bone factures in utero) type III some defects visible at birth but latter progressive deformities

occur; growth retardation; common the teeth abnormalities type IV similar to type I, but sclerae are normal; colagen forms delicate

thin fibrils (improper cross-linking)

Osteopetrosis (marble bone disease/Albers-Schnberg bone disease) excessive density (blocklite) of all bones (but mechanically weak)

with marrow cavity obliteration ( anemia) failure of bone remodelling (osteoclastic activity)

retention of the primary spongiosum with cartilage cores lack of funnelization of the metaphysis thickened cortex

thickened cortices with reduced marrow cavities, persistence of woven bone and lack of lamellar bone, almost always cartilage core could be observed

delayed teeth eruption

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Osteopetrosis tooth extraction commonly followed by osteomyelitis long bones have Erlenmeyer flask (widened metaphysis

and diaphysis) on x-ray no distinction between cortical and medullary bone;

almost invisible tooth roots mandible more common involved then maxilla two types:

early in life (AR), multiple fractures with early death (before puberty) benign (AD), sometimes with mild symptoms and very late diagnosis

Cleidocranial dysplasia (dysostosis)

many bones abnormalities, mainly skull, jaw and clavicles (lack) with dental abnormalities

AD flat skull, prominent frontal, parietal and occipital bones, opened fontanelles and sutures high and narrow arched palate with underdevelopment of maxilla retained deciduous teeth and or non-erupted permanent dentition supernumerary teeth (mandibular premolar and incisor region)

Achondroplasia the most common form of dwarfism (F = 125 cm, and M = 131 cm) no mental retardation, and normal average life span abnormal endochondral ossification (defect/absence of the zone

of provisional ossification of the cartilage in the epiphyses and the skull base middle third of the face is retrusive)

but intramembranous ossification is undisturbed and periosteum function is normal bones are very short but thick

the trunk and skull (sometimes large) of normal size but the extremities are extremely short; sometimes severe kyphoscoliosis develops

AD or fresh mutations (most common) FIBROOSSEUS LESIONS

Fibrous dysplasia of the bone (1)

Etiology unknown developmental defect?

Disorganized mixture of fibrous and osseus elements in the interior of affected bones

In 5% of patients McCune-Albright syndrome (bone lesions + skin pigmentation + endocrine abnormalities)

Fibrous dysplasia of the bone (2a)

monostotic more common than polyostotic 2nd and 3rd decade, M=F most frequently extremities > ribs > skull (jaws maxilla > mandible)

usually present at childhood or adolescents

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Fibrous dysplasia of the bone (2b)

presentation: painless asymmetric enlargement of poorly

circumscribed mass even on x-ray (may mimic a cyst)

usually placed more buccally than lingually or palatally

maxillary masses (distal to the canine fossa) often lead to extension to the sinus, zygomatic processus, and floor of the orbit

mandible masses (molar and premolar region) they may lead to tooth abnormalities

Fibrous dysplasia of the bone (2d)

morphology: replacement of normal bone by fibrous tissue

(sometimes more cellular or plenty of thick collagen bundles) with islands of trabeculae of metaplastic bone (irregular shape, coarse-fibred woven bone with varying amounts of osteoid

in jaw lesion could be more variable than in long bones with spheroidal areas of calcification resembling cementum

osteclastic and osteoblastic activity may be seen

Fibrous dysplasia of the bone (2c) polyostotic F:M = 3:1 25% of patients have exhibit disease in more than half of

the skeleton including facila bones mainly in long bones (lower extremities) than in skull

vertebrae, ribs and pelvis

involve one bone segmentally or one side of the body diagnosed in childhood (pathologic fractures of deformed

bones), accompanied (sometimes) by caf au lait spots (coast of

Maine) Albright syndrome (endocrine disfunction acromegaly, Cushing syndrome, hyperthyroidism, vitamin D-resistant rickets)

Cherubism (1) rare disease, AD, M:F = 2:1 at the age of 2-4 years, painless usually asymmetric

enlargement of mandible (less often maxilla) that stops at the age of 7, then regression of face deformity occurs

characteristically chubby face (fullness of the chicks and enlarged submandibular lymph nodes) is observed

eyes upturn to heavens (visible rim of sclera beneath the iris)

premature loss of deciduous teeth with failure of development of many permanent ones

on x-rays multiple radiolucent sharply demarcated lesions

Cherubism (2) morphology: - cellular and vascular fibrous tissue containing

multinucleated giant cells

Osteomyelitis

differs from the inflammation of the long bones: usually a localized condition associtaed with periodontal infection usually involves otherwise healthy adults often caused by anaerobes

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acute suppurative (rarefying) osteomyelitis

now rare adult males presented with pain, swelling, paresthesia of the lip, pyrexia, and

mobility of the teeth, trismus following teeth infection (mixed flora, but St. aureus is a rare

factor) or local trauma mandible is predisposed for it risk factors: DM, leukaemia, bone diseases (osteopetrosis,

Pagets disease, radiation-damage) tissue necrosis develops because of thrombosis in surrounding

blood supply, then marrow cavity is filled with pus (sometimes with sequestrum)

latter granulation tissue is developing x-rays: lytic bone destruction (after one week) and later

periosteal bone formation

chronic suppurative (rarefying) osteomyelitis

may follow an acute osteomyelitis or start as chronic from the beginning (tuberculosis, syphilis or actinomycosis, but all of those are now rare)

symptoms are more insidious

marrow cavity contains granulation tissue rather than pus

focal sclerosing osteomyelitis (condensing/sclerosing osteitis)

a special type of chronicc osteomyelitis at the apex of the tooth (first permanent

molar) patients usually before the age of 20 usually asymptomatic bone reaction to periodontal infection fibrosed marrow with some lymphocytes and

plasma cells and local increased thickness of bone trabeculae

diffuse sclerosing osteomyelitis

also a special type of chronic ostemyoelitis as focsal sclerosis osteomyleitis but occurs in

patients with widespread periodontitis occurs in elderly patients (blacks) often bilateral, mandible or maxilla sometimes with fistulas formation

chronic osteomyelitis with proliferative periostitis

(Garres osteomyelitis; periostitis ossificans) exclusively in mandible children and young adults spread of inflammation (apical, soft tissue,

mechanical irritation) with a proliferation reaction of the periosteum (visible on x-rays)

radiation osteomyelitis (osteoradionecrosis)

radiation induced occlusion of the vessels asymptomatic bone necrosis rapid spread of infection form surrounding structures painful necrosis of the bone

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chemical osteomytelitis

now rare associated with phosphorus and mercury

poisons

pulse granuloma/vegetable granuloma

chronic periostitis associated with hyaline bodies (ring-shaped) accompanied by giant cells

METABOLIC AND ENDOCRINE BONE DISAESES

OSTEOPOROSIS Bone diseases

osteoporosis decreased bone strength reduction in the bone mass (density) increasing porosity of the

skeleton fractures (1.5 mln fractures a year in USA), mainly: vertebral and hip

in USA affects > 10 mln patients (8 mln and 2 mln ), but additional 18 mln have decreased bone mass

Def: reduction in the bone mass (density) or the presence of fragility

fractures most women meet criteria by the age 70 to 80

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osteoporosis Consequences:

in USA about 300,000 hip fractures a year (about 14% of risk for 50-year-old white individual and about 5%

risk for same ; related African Americans have a half risk rate)

deep vein thrombosis

Pulmonary embolism (20-50%)

5-20% mortality (in 12 months after surgery)

osteoporosis vertebral crush fractures 700,000 a year (less clinically

significant, some asymptomatic) multiple height loss, kyphosis, secondary pain, altered biomechanics of the back, pulmonary restrictive diseases (thoracic) or abdominal symptoms such as constipation, distension and early satiety (lumbar region)

wrist fractures about 250,000 a year other (e.g. humerus, pelvis) fractures 300.000 a year

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osteoporosis Primary:

Postmenopausal Senile

Secondary: Endocrine dis:

Hyperparathyroidisms Hypo/hyperthyroidisms Hypogonadism Pituitary tu. DM type 1 Addisons disease

Neoplasia: Multiple myeloma carcinomatosis

Secondary (cd): drugs:

Anticoagulants Chemotherapy Corticosteroids Anticonvulsants Alcohol

GI diseases: Malnutrition Malabsorption Hepatic insufficiency Deficiency of vit C/D idiopathic

osteoporosis Miclellaneous: - Osteogenesis imperfecta - Immobilisation - Pulmonanry diseases - Homocystynuria - Anemia Other causes: dementia Parkinsons disease multiple sclerosis

osteoporosis peak bone density early adulthood (it could be stable during age

30 to 45, latter we observe - imbalance between the bone resorption and formation) according to genes, life-style, nutrition

heritability responds to from 50 to 80% for bone density, candidate genes:

vit. D rec. type I collagen estrogen rec. IL-6 IGF-I locus on chr. 11 associated with high bone mass (extreme bone mass in

patients with mutation LRP5 [ LDL receptor related protein])

osteoporosis hormones that have influence on bone remodeling: estrogens androgens vit. D PTH and produced locally

IGF-I and II TGF- PTHrP ILs prostaglandins TNF and cytokines (RANK, and osteoprotegerin ligand)

osteoporosis other causes: inadequate calcium intake during growth in adult life inadequate calcium intake (recommended 1000-1200 mg/d;

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RICKETS/OSTEOMALACIA Bone diseases

rickets and osteomalacia

deficiency or resistance to vitamin D failure of mineralization of bone and cartilage enamel hypoplasia, increased width of predentine, large amounts of

interglobular dentine delayed dentition, severe dental caries, enamel defects lack of growth of vertical ramus of the mandible

PARATHYROID GLANDS: ANATOMY AND PHYSIOLOGY

- - the parathyroids arise from the third and

fourth branchial clefts - 3 or 4 but 5 or 6 too - each 3-4 mm and weigh 35 mg each

HYPERPARATHYROIDISM ("stone and bone disease")

PRIMARY HYPERPARATHYROIDISM due to disease of the parathyroid glands.

80-85%... parathyroid "adenoma" ("single gland disease") 10-15%... parathyroid "hyperplasia" ("multiple gland disease", usually all four glands) maybe 1%... parathyroid carcinoma (I think this traditional number is high)

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Primary hyperthyroidism

Symptoms and signs: gastric ulcers (5%; hypercalcemia from any cause enhances

gastrin secretion) hypertension (50%, cured by parathyroid surgery only if the

kidney is undamaged) pancreatitis (occasionally) pseudogout (occasionally)

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Pathology lecture 6