Robbins Flashcards
What is the inorganic mineral component of bone?
Calcium hydroxyapatite
What is the role of calcium hydroxyapatite in bone?
Strength + hardness to bone
Storehouse of 99% of bodys calcium + 85% phosphorus + 65% magnesium
What cells express RANK?
Preosteoclasts + mature osteoclsts
RANK Ligand is expressed by what cells?
Osteoblasts and marrow stromal cells
Stimulation of RANK by its Ligand leads to?
Activation of transcription of factor NF-kB, which drives expression of genes to stimulate osteoclast formation + diff + function + survival
What up upregulates RANKL?
Osteoclast stimulating factors
Overall function of RANK + Ligand?
Up-reguate OSTEOCLAST activity
what is OPGs function?
Osteoprotegerin–> Blocks RANKL from binding to RANK
What competitively binds to RANKL to prevent bone resorption?
OPG
Problems in migration of mesenchymal cells and formation of condensations is called?
Dysostoses –> results from Homeobox mutations
Mutations interfering with bone or cartilage formation/ growth and/or maintenance of normal matrix?
Dysplasia (not precancerous)
“Brittle bone disease?”
Osteogenesis imperfecta
Genetic disorder caused by defective synthesis of alpha 1 +2 chains of type I collagen?
Osteogenesis imperfecta
What is the role of type I collagen?
it is a main component of Matrix all over the body
Fundemental abnormality is Too little bone–> extreme skeletal fragility?
Osteogenesis imperfect
What is a pathooneumonic characteristic of Osteogenesis imperfecta Type I patients?
BLUE sclera
What is pg of pt with pathopneumonic BLUE SCLERA?
OI–> caused by decreased collagen content causing transparency allowing underlying choroid to be seen
What are some deficits attributed to OI?
Hearing loss–> conduction defect in middle ear and inner ear bones
Small misshapen teeth–> dentin deficiency
BLUE SCLERA + bone disease?
Osteogenesis Imperfecta
What is the most common form of dwarfism?
Achondroplasia
What is Pg of achondroplasia (dwarfism)?
Activating point mutation in FGFR3
What is the function of FGFR3?
inhibits the proliferation and function of growth plate chondrocytes–> normal epiphyseal plate is suppressed + long bone is Severely stunted
Disproportionate shortening of proximal extremities+ bowing legs+ frontal bossing+ midface hypoplasia?
Dwarfism (achondroplasia)
Genetic disorders characterized by defective OSTEOCLAST-mediated bone resorprtion?
Osteopetrosis
What is “bone like stone disorder?”
Osteopetrosis–> bone are dense, solid, and stone like.
What are some of the abnormalities in Ostepetrosis which inhibit Osteoclast activity to resorb bone?
Carbonic anhydrase II deficiency
Proton pump deficiency
Chloride channel defect
What disease makes pt susceptible to fractures + cranial nerve palsies due to compression from shrunken foramina?
Osteopetrosis
Causes recurrent infection due to reduced BM size + activity and hepatosplenomegaly due to extramedullar hematopoiesis?
Osteopetrosis
Osteoclasts are derived from what precursors?
Marrow MONOCYTE precursors
Tx for Osteopetrosis?
Hemato[oietic stem cell transplant to repopulate progenitor cells capable of differentiating into OSTEOCLASTS
Defective osteoclast function causing architecturally weak and bowing bone from defective bone resorption?
Osteopetrosis
Mutation in type I collagen (alpha 1+2 chains)?
Osteogenesis imperfecta
Acquired condition characterized by reduced bone mass?
Osteoporosis
What are main causes of primary Osteoporosis?
Aging –> senile osteoporosis
Postmenopausal–> decreased Estrogen exacerbates bone loss
What are two main locations most susceptible to bone loss in osteoporosis?
Spine + Femoral neck
Causes thinned cortices + dilated haversian canals + loss of interconnections?
Osteoporosis
What is osteolytic activity and mineral content of bone in Osteoporosis?
Osteolytic activity is present (not increased)
Mineral content NORMAL
Osteoporosis occurs when?
the balance btwn Bone formation (osteoblasts) and Bone resorption (osteoclasts) is tilted in favor of RESORPTION
Age related causes of Osteoporosis?
Osteoblast activity progressively diminishes + extracellular matrix growth factors diminish w. time
What is the osteoblast vs. osteoclast activity level in senile osteoporosis?
Osteoblasts–> diminished function
Osteoclasts–> NORMAL function
Decline in estrogen is associated with?
accelerated cortical bone and trabecular bone LOSS
Over 30-40 yo, can result in what % of cortical vs trabecular bone loss?
Cortical -> 35 % loss
Trabecular–> 50% loss
What is the Pg of Estrogen decline and bone loss?
Decreased estrogen–> increased Cytokine production (IL-1 + TNF + IL-6) –> Stimulate RANK and suppress OPG production
Estrogen therapy benefits and consequences for postmenopausal women?
May ameliorate bone loss
BUT Increases RISK for CV issues
Causes increased IL-1 + IL-6 + TNF levels leading to increased RANK actions and increased Osteolytic activity?
Menopause–> DECREASED ESTROGEN
Decreased replicative activity of osteoprogenitor cells and decreased osteoblast activity + decreased matrix growth factors?
Aging related Osteoporosis
How does physical activity affect bone?
Mechanical force stimulates bone remodeling–> Resistant exercises (weight lifting) are more affective at increasing bone mass
What are some secondary causes of osteoporosis?
Prolonged glucocorticoid use–> increases bone resorption and reduces bone synthesis
Cigarettes + alcohol–> reduce bone mass
MCC complications of osteoporosis?
Thoracic or lumbar VB fractures leading to Kyphoscoliosis
What are MCC consequences of Femoral neck or pelvis or spinal fractures?
PE or pneumonia
What are two tests used for determining Osteoporosis?
Dual energy absorptiometry and quantitative CT
What are some Tx of osteoporosis that target reducing Osteoclast activity?
Antiresorptives–> Bisphosphonates + calcitonin+ estrogen + Denosumab
Main anabolic agent targeted to stimulate osteoblastic activity when treating osteoporosis?
Parathyroid hormone or analogues
Bone disease resulting in Gain in bone mass but bone is disordered and weak so they become enlarged and misshapen?
Pagets (Osteitis Deformans)
What are the 3 characteristic stages of Osteitis Defomans?
Osteolytic stage
Exuberant bone formation stage
Exhaustion stage (osteosclerotic)
What populations have a high prevalence of Pagets disease?
Europe
Australia
New Zealand
USA
Newly formed bone remodeled into abnormal lamellar bone with MOSAIC pattern (Jigsaw puzzle)?
Pagets disease
What is the Pg of Osteitis Deformans?
Inflammatory process caused by underlying PARAMYXOVIRUS infection in osteoclasts
What is the role of Paramyxovirus infection in Osteitis deformans?
Virus causing production of IL-1 + IL-6 + M-CSF–> all of which Activate Osteoclasts
Disease can be monostotic (lytic lesion in Tibia, femur, humerus…) or Polystotic (lesions Proximal femur or axial skeleton)?
Osteitis Deformans
Elevated serum alkaline phosphatase and increased Urinary Hydorxyproline reflects what?
Continuous or excess BONE Turnover
What is a consequence of Polyostotic Pagets disease?
Hypervascularity resulting in High-output CHF
Causes Brittle bone “Chalk stick fractures?”
Osteitis Deformans
Pagets disease dreaded complications and possible treatment?
Comp–> Sarcoma
Tx: Bisphosphonates to stop bone resorption
Impaired mineralization resulting in unmineralized matrix?
Osteomalacia or Rickets
Hypovitaminosis D
What is the difference btwn Osteoporosis and Osteomalacia?
Osteoporosis–> Bone has NORMAL mineral content but decreased mass
Osteomalacia–> Abnormal mineral content
Roles of PTH?
Osteoclast activation-> increases RANKL express
Increased Renal Ca+ resorption
Increased Phosphate excretion
Increased 1,25(OH)2 Vit D
What is the main action of PTH?
Elevation of serum Calcium
How does Chronic renal failure cause Osteodystrophy?
Inadequate 1,25(OH) D production
Hyperphosphatemia–> suppresses alpha 1 hydroxylase
What is the hallmark of Excess PTH?
Increased Osteoclastic activity
Causes bone resorption in subperiosteal regions most pronounced @ Lateral Middle Phalanges of 2nd + 3rd fingers?
Excess PTH
What is seen microscopically in excess PTH?
Osteoclasts boring into center of bony trabeculae
And expanding Haversian canals
What is Osteitis fibrosa cystica?
Cystic changes caused by excess PTH
What contributes to osteonecrosis?
Vascular compression Steroid use Thrombembolic disease (Caissons) SCD Vasculitis
What is Osteomyelitis and MCC?
Inflammation of bone marrow
MCC–> pyogenic bacteria + TB
What is the overall MCC of pyogenic Osteomyelitis?
S. aureus
What organisms are important causes of Neonatal osteomyelitis?
E. coli + group B strep
What is the MCC pathogen in Osteomyelitis + SCD?
Salmonella
Radiologic finding reveals: destructive lytic focus surrounded by edema and sclerotic rim?
Osteomyelitis
What are some complications of Osteomyelitis?
Pathologic fractures
2nd Amyloidosis
Endocarditis
SCC
MCC of infection in the vertebral bodies causing collapse and deformities from posterior dislocation?
POTT disease–> TB Osteomyelitis
Pt with Pott disease and psoas muscle abscess?
TB osteomyelitis
What is the most common primary bone tumor?
Osteosarcoma
Tumor arising from Knee in adolescent MALE child?
Osteosarcoma
MId to late adult with tumor involving trunk, limb girdle, or proximal long bones?
Chondrosarcoma
What conditions are associated with Osteosarcoma?
Li-Fraumeni (TP53 mutation)
Retinoblastoma (Rb mutation)
Bone infarcts
Paget disease
Benign slow growing, solitary, hard lesion of Head or Neck in middle aged man?
Osteoma
Teenage male w. < 2cm lesion arising from beneath periosteum or within cortex in proximal Femur/ Tibia?
Osteoid Osteoma
Most commonly presents w/ localized pain that is severe at Night and is relieved by Aspirin?
Osteoid Osteoma
Teenager with lesion in vertebral column that are >2cm and have non-localized pain that does NOT respond to aspirin?
Osteoblastoma
Bone-producing malignant mesenchymal tumor?
Osteosarcoma
Morphology: Gray-white exhibiting hemorrhage and cystic degeneration. With Large and varying shaped cells + bizarre tumor giant cells?
Osteosarcoma
What is essential for the Diagnosis of Osteosarcoma?
Production of mineralized or unmineralized bone by malignant cells
What is the MCC mutation in Osteosarcoma?
RB gene mutation
CXR shows a TRIANGULAR shadow btwn cortex and raised periosteum?
Codman triangle–> Osteosarcoma
MC location of Osteosarcoma metastasis?
LUNG
Child w. multiple bony lesions and known EXT1 or EXT2 mutations?
Multiple hereditary Osteochondromas
What do EXT1 or EXT2 genes encode?
Glycosyltransferases essential for polymerizing heparin sulfate–> IMPORTANT for cartilage
What tumor grows around Knee or metaphysis of long bones and stops growing once normal growth of bone has Halted?
Osteochondroma
What is a benign neoplasm of hyaline cartilage arising within medulla called?
Endochondroma
Benign neoplasm of hyaline cartilage arising from bone surface is called?
Juxtacortical chondromas
Chondromas most often affecte what bones?
Short tubular bones of hands and feet
Disease characterized by multiple chondromas involving ONE side of the body?
Ollier disease
Disease characterized by multiple chondromas associated w/ soft tissue spindle cells hemangiomas?
Maffucci syndrome–> associated w. Ovarian carcinomas and Brain glioma
What mutation is found in both Ollier + Maffucci syndromes and also AML and gliomas?
IDH1 and IDH2 enzyme mutation
IDH= isocitrate dehydrogenase
X-ray showing well-circumscribed oval lucencies surrounded by thin rims of bone (O-ring sign)?
Chondroma
Rapidly growing painful Lesions commonly arising from Pelvis, Shoulder, and ribs?
Chondrosarcoma
Chondrosarcomas larger that what size are more aggressive and where do they metastasize?
> 10cm
LUNGS + Skeleton
Lesion showing benign Fibroblasts and activated macrophages exhibiting a STORIFORM (pinwheel) pattern + hemorrhage?
Fibrous cortical defects
Benign tumor in which all components of bone are present but fail to differentiate into mature structures?
Fibrous dysplasia
Polyostotic disease associated w. cafe au lait skin and endocrine abnormalities precocious puberty?
McCune-Albright syndrome –> Fibrous dysplasia
What is the mutation present in all forms of Fibrous dysplasia?
GNAS gene mutation-> Constitutively active Gs protein
20-30 yo with tumor located in RIBS or JAW bones?
Fibrous dysplasia
Large masses that expand and distort bones. Cells exhibit curved trabeculae of woven bone (CHINESE characters)?
Fibrous dysplasia
X-ray showing Ground Glass appearance of well defined bone lesions?
Fibrous dysplasia
2nd MC tumor of undifferentiated neural cells occurring in White pt 10-15 yo?
Ewing Sarcoma
What is the MC chromosomal abnormality associated with Ewing Sarcoma?
Translocation (11;22)
Cells having scant glycogen-rich cytoplasm and presence of Tumor cells circled about a central fibrillary space indicating neural differentiation?
Homer-Wright rosettes= Ewing Sarcoma
Painful enlarging mass in Diaphyses of Femur or Pelvic flat bones and characteristic Onion-skin pattern of bone deposition?
Ewing Sarcoma
Tumor of Osteoblast precursors located in the Epiphysis of Femur or Tibia (knee), “Soap bubble” appearance on X-ray?
Giant cell tumor
What are the 4 MC metastases to bone in Adult pts?
Prostate
Breast
Kidney
Lung
What are MC sources of bony metastases in Children?
Neuroblastoma WIlms tumor Osteosarcoma Ewing sarcoma Rhabdomyosarcoma
What sources of bony metastases cause Lytic lesions due to secretion of PGs + IL + PTH related proteins that stimulate Osteoclasts?
Kidney
Lung
Melanoma
What bony metastases elicit an Osteoblastic response?
Prostate adenocarcinoma
Curvilinear trabeculae of woven bones surrounded by benign Fibroblasts?
Fibrous dysplasia
Islands of woven bone, typically involving the proximal Femur or Tibia?
Osteoid Osteoma
Cartilage capped outgrowth at Epiphyseal growth plate?
Osteochondroma
NON inflammatory Degeneration of articular cartilage?
Osteoarthritis
Fibrillation and cracking of matrix occurs as superficial layers of cartilage are degraded and Osteophyte growth occur in what disease?
Osteoarthritis
50-60 yo with deep aching pain that is exacerbated by use, morning stiffness would have what pathoneumonic JOINT involvement?
Osteoarthritis–> PIP + DIP
What is a Heberden node?
Osteophytes located in the DIP joints of Women with Osteoarthritis
Disease characterized by CD4 mediated inflammation and Anti-antibodies against Cyclic citrullinated peptides (CCPs)?
Rheumatoid arthritis
What are some of targets for Anti-Abs in RA?
Citrullinated fibrinogen Type II collagen alpha enolase vimentin Immune complex deposition may occur
What is IgM that binds to the Fc portion of self IgG and form immune complexes that deposit in joints?
RA–> Rheumatoid factor
Symmetric arthritis affecting MCP and PIP joints?
RA
Disease characterized by chronic papillary synovitis w. synovial cell hyperplasia, CD4+ cells, plasma cells, macrophage, and PMN infiltrates?
RA
What is Proliferation of synovial lining cells mixed with inflammatory cells, granulation tissue, and fibrous connective tissue?
Pannus of RA
Radiology showing joint effusions and juxtaarticular osteopenia with erosions and narrowing of joint spaces and loss of articular cartilage?
RA
Characterized by central focus of fibrinoid necrosis surrounded by a palisade of macrophages and rimmed granulation tissue and lymphocytes?
Rheumatoid nodules
What are some complications of RA?
acute necrotizing vasculitis Fibrinous pleuritis Pericarditis Interstitial fibrosis Ocular changes Sjogren syndrome
Pathological changes in ligamentous attachments to bone, absences of rheumatoid factor, and involvement of Sacroiliac joints?
Seronegative spondyloarthropathies
*Ankylosing spondylitis
Monosodium urate crystals precipitate from supersaturated body fluids and induce inflammatory reaction?
Gout
What is a tophi?
Large crystalline aggregates surrounded by inflammatory lymphocytes, macrophages, and foreign body giant cells trying to engulf them
Tophi are pathopneumonic for?
Gout
What is a major organ complication associated with urate deposition?
Gouty Nephropathy
What enzyme deficiency is associated with overproduction of Uric acid?
HGPRT deficiency– > Lesch-Nyhan syndrome
What is the Pg of Gout?
Excess uric acid-> urate crystals-> activation of complement or phagocytksed-> induce IL-1 production-> PMNs recruited-> LTB4 and protease released causing damage
What HLA subtype is associated with RA and DB?
HLA- DR4
“Cant see, Cant pee, Cant climb tree?”
Reactive arthritis triad–> conjunctivitis + urethritis+ arthritis
Joints with dislodged pieces of cartilage and subchondral bone forming loose bodies (“joint mice”) causing pain and restricting movement?
Osteoarthritis
What is pseudpgout?
Chondorcalcinosis–> Deposition of Calcium pyrophosphate crystals
What are the crystals in psuedogout made out of?
Calcium pyrophosphate
Describe the morphology of pseudogout crystals?
Rhomboid shaped
weak birefringent–> Blue
Pseudogout most commonly affect what joints?
Menisci, IV discs, Articular sufaces >50yo
MCC of suppurative arthritis in <2yo?
H. flu
MCC of suppurative arthritis in children?
S. aureus
MCC of suppurative arthritis in young adults (sexually active women)?
Gonococcus
MCC of suppurative arthritis in SCD pt?
Salmonella
Pt w. “sudden onset f pain, redness, swelling, restricted movement, and fever?”
Suppurative arthritis
What soft tissue tumor has high prevalence in children?
Rhabdomyosarcoma
Which soft tissue tumors have high prevalence in young adults and late adults?
Synovial sarcoma – young
Liposarcoma + pleomorphic fibroblastic sarcomas –> late
Most common benign tumor in adults presenting as slowly enlarging, painless, mobile mass?
Lipomas–> non-differentiated adipocytes
Rapidly growing solitary mass of Fibroblastic proliferation occurring in forearm, chest, or back following trauma?
Nodular fasciitis
Dupuytrens contracture and peyronies disease are examples of locally aggressive fibroblast proliferation associated with what genetics?
Superficial Fibromatoses (trisomy 3, 8)
Desmoid tumors arise in abdominal wall and muscles of trunk and are associated with what disease/ genetics?
Gardeners syndrome
APC or B catenin mutations
Proliferation of MYOfibroblasts
Malignant spindle cells arranged in “herringbone pattern?”
Fibrosarcoma
Histological appearance shows poorly differentiated sarcoma with bizarre multinucleate cells and storiform architecture?
Pleomorphic fibroblastic sarcoma
What sarcoma is associated with a t(2;13)?
Rhabdomyosarcoma
Histology showing sarcoma with spindle cells having “Cigar shaped nuclei?”
Leiomyosarcoma
Axonal degeneration is associated with 2nd myelin loss?
Wallerian degeneration
* followed by regeneration and myelination of new axon
Rapidly progressive demyelinating disorder affecting motor axons that result in Ascending weakness that lead to respiratory muscle failure?
Guillian Barre
What is the Pg of Guillian Barre?
Autoimmune response to infections Campylobacter jejuni EBV CMV HIV
Tx of Guillian barre?
Plasmapheresis or IV Ig
Symmetrical demyelination of motor and sensory neurons caused by Autoimmune attacks, associated with SLE and HIV following a chronic relapsing or progressive course?
Chronic inflammatory demyelinating polyneuropathy
Tx for Chronic inflammatory demyelinating polyneuropathy?
Plasmapheresis or IV Ig
Autonomic neuropathy and distal symmetric sensorimotor polyneuropathy is MC in what pathology?
Diabetes
Mononeuritis multiplex with a painful asymmetric mixed sensory and motor peripheral neuropathy is seen in what pathology?
Vasculitis–> Polyarteritis nodosa, Churg- Strauss, Wegners
MCC of peripheral neuropathy?
Diabetes
Autoimmune antibodies blocking function of postsynaptic ACh receptors at motor end plate resulting in degradation and depletion of receptors?
Myasthenia Gravis
What are the 2 MC conditions associated with Myasthenia Gravis?
60%–> Thymic hyperplasia
20%–> Thymoma
Pt presenting with Ptosis and diplopia is most often associated with what neuromuscular disorder?
Myasthenia Gravis
Treatment for Myasthenia Gravis?
AChE inhibitors
immunosuppressives
Plasmapheresis
Thymectomy
Caused by autoantibodies against Presynaptic Ca+ channels reducing the release of ACh?
Lamber-Eaton Syndrome
Repetitive use of electrophysiologic stimulation of muscles increases/ decreases severity in what diseases?
Increases–> myasthenia gravis
decreases–> Lambert-Eaton syndrome
Eaton-Lambert syndrome is associated with what pathology and what is the treatment?
Small cell carcinoma LUNG
Tx: Plasmapheresis + immunosuppression
** AChE inhibitor do NOT work
What two infectious organisms are associated with neural transmission defects?
Clostridium botulinum–> inhibits ACh release
Clostridium tetani–> increased ACh release
What is the difference btwn type I & type II muscle fibers?
Type I–> slow twitch “aerobic”
Type II–> Fast twitch “anaerobic”
Prolonged disuse and Glucocorticoid use affect predominately which muscle fibers?
Atrophy of Type II
Characterized by ongoing myofiber necrosis and regeneration and progressive replacement of muscle tissue with fibrosis and fat?
DMD and BMD
X linked recessive disease caused by Frameshift mutation causing Absent dystrophin protein?
DMD
BMD Pg?
Frameshift mutation of X chromosome== ABNORMAL dystrophin protein
Where is the dystrophin gene found?
Short arm of X chromosome
What is the role of dystrophin protein?
Stabilization during contraction
Possible signaling
Child presenting with clumsiness, muscle weakness, and pseudo-hypertrophy of calf muscle?
DMD or BMD
What are some of the complications of DMD?
Heart failure
Arrhythmias
increased CK levels due to muscle breakdown
Respiratory failure or pneumonia = Death
Characterized by “sustained involuntary contraction of group of muscles” causing stiffness and difficulty releasing grip?
Myotonic dystrophy
What is the genetics of myotonic dystrophy?
TRINUCLEOTIDE repeat disorder–> AD mutation in Dystrophia myotonica protein kinase (DMPK)
Caused by CTG repeats in the 3’ untranslated end of DMPK mRNA?
Myotonic dystrophy
MC primary malignant bone tumor: knee joint?
Osteosarcoma
Adults + cartilage + trunk and limbs?
Chondrosarcoma
Peripheral primitive neruoectodermal tumor, children and young adults, Diaphysis of bone?
Ewing’s sarcoma
Immunological disorders with LUPUS?
anti-dsDNA (histones, RNA proteins, nucleolar Ags)
Anti-Sm
antiphospholipid antibodies
Lupus anti-coagulant
Anti-SS-A (RO) + Anti-SS-B (La) are specific for what disease?
Sjogren syndrome
Anti-scl-70 (topo I) ?
Systemic sclerosis
Anti-centromere antibodies?
Scleroderma (CREST syndrome)
Anti-Jo 1 antibodies?
Inflammatory myopathies
Characterized with calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia?
Crest syndrom (systemic sclerosis)
