Pathology lecture 6
-
Upload
micke-rodriguez -
Category
Documents
-
view
226 -
download
2
description
Transcript of Pathology lecture 6
-
27.05.2015
1
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
-
27.05.2015
2
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)
-
27.05.2015
3
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
-
27.05.2015
4
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.
-
27.05.2015
5
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
-
27.05.2015
6
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
-
27.05.2015
7
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
-
27.05.2015
8
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
-
27.05.2015
9
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
-
27.05.2015
10
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
-
27.05.2015
11
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;
-
27.05.2015
12
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)
-
27.05.2015
13
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)