2015
muscle
Muscle diseases
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
27.05.2015
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
27.05.2015
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
CONGENITAL MYOPATHIES
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)
27.05.2015
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
27.05.2015
Osteogenesis imperfecta
Osteopetrosis
Cleidocranial dysplasia (dysostosis)
Achondroplasia
Fibroosseus diseases
Cherubism
Osteogenesis imperfecta
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
27.05.2015
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)
FIBROOSSEUS LESIONS
27.05.2015
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)
Cherubism (2)
Osteomyelitis
morphology:
- cellular and vascular fibrous tissue containing
multinucleated giant cells
27.05.2015
radiation osteomyelitis
(osteoradionecrosis)
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)
27.05.2015
chemical osteomytelitis
now rare
associated with phosphorus and mercury
poisons
Bone diseases
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
27.05.2015
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)
10
27.05.2015
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:
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)
11
27.05.2015
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)
12
27.05.2015
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)
13