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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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Duchenne Muscular Dystrophy (2)
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)
Duchenne Muscular Dystrophy (3)
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
Duchenne Muscular Dystrophy (4)
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)
Duchenne Muscular Dystrophy (5)
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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Myotonic Dystrophy (2)
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
Myotonic Dystrophy (3)
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
CONGENITAL MYOPATHIES
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
CONGENITAL MYOPATHIES
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)
CONGENITAL MYOPATHIES
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
INFLAMMATORY MYOPATHIES
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
INFLAMMATORY MYOPATHIES
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.
Myasthenia gravis (3)
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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Myasthenia gravis (4)
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)