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27.05.

2015

muscle
Muscle diseases

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)

Duchenne Muscular Dystrophy (5)

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

Myotonic Dystrophy (1)

milder form of DMD


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

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)

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

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

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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 complementmediated 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.

Inherited and developmental diseases

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

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)

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.

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

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:

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)

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

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)

Fibrous dysplasia of the bone (1)


Etiology unknown developmental defect?
Disorganized mixture of fibrous and osseus
elements in the interior
of affected bones

FIBROOSSEUS LESIONS

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

In 5% of patients McCune-Albright syndrome


(bone lesions + skin pigmentation + endocrine
abnormalities)

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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 (2c)

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

Cherubism (1)

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)

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)

Osteomyelitis

morphology:
- cellular and vascular fibrous tissue containing
multinucleated giant cells

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

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

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

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

radiation osteomyelitis
(osteoradionecrosis)

(Garres osteomyelitis; periostitis ossificans)

radiation induced occlusion of the vessels


asymptomatic bone necrosis rapid
spread of infection form surrounding
structures painful necrosis of the bone

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)

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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

Bone diseases

METABOLIC AND ENDOCRINE


BONE DISAESES

OSTEOPOROSIS

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

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)

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

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;
<400mg/d detrimental for skeleton) secondary hyperparathyroidism
vit D deficiency (elderly, living in northern latitudes, poor nutrition,
malabsorption, chronic liver disease, chronic kidney disease) compensatory
hyperparathyroidism
estrogen function cessation
physical activity (inactivity, bed rest and paralysis versus athletes)
chronic diseases (nutrition + reduced physical activity + factors influencing
bone remodeling)
Medication
cigarette smoking ( toxic effect on osteoblasts; modifying estrogen
activity; and secondary effects: respiratory illnesses, frailty, decreased
exercise, poor nutrition and medication [eg. glucocorticoids])

osteoporosis
morphology:
in trabecular bone, if the osteoclasts penetrate trabeculae, they
leave no template for new born formation to occur ( rapid bone
loss)
in cortical bone, increased activation of remodeling creates more
porous bone
micro-fractures (collapse of vertebrae)
thinned cortex
Haversian systems widened
estrogen levels secretion of IL-1 (stimulator of osteoclast
recruitment and activity)

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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
Bone diseases

RICKETS/OSTEOMALACIA

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

Primary hyperthyroidism
is a common clinical problem
1 person in 1000 will need parathyroid
surgery during his or her lifetime
Patient with MEN I has about an 85%
lifetime chance of getting primary
hyperparathyroidism;
with MEN II has about a 20% chance
(usually hyperplasias).

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)
<1%... iatrogenic seeding causing lots of little glands:
hypercalcemia caused by production of parathyroid-hormone-like
activity (PTH-rP) by cancers (eg. squamous lung cancer)
"pseudohyperparathyroidism"

Primary hyperthyroidism
Symptoms and signs:
Elevated serum calcium on routine screening (most common
now)
Mental changes (depression, psychosis)
kidney stones (the commonest presentation in the past)
nephrocalcinosis (metastatic calcification in the tubular
basement membranes with eventual damage to the tubules)
bone changes (first osteomalacia, then widespread involvement
of the skeleton by increased osteoclastic activity especially in the
centers of trabeculae; finally cystic lesions variously known as
"osteitis fibrosa cystica", "von Recklinghausen's disease of
bone", or "brown tumors." All this heals after the
hyperparathyroidism is fixed.)
most extreme: Calciphylaxis (metastatic calcification of the skin,
with horrible ulcers and breakdown)

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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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