Path 2 Flashcards
dermatomyositis affects? classic vs revised model
skin & muscles. humoral attack on muscle capillaries and arterioles –> MAC deposits in perivascular sites –> capillaries destroyed and muscle fibers atrophy vs overprod of IFN-inducible proteins –> high type I IFN –> endothelial cells and muscle fibers injured –> perifascicular atrophy
skin vs muscle vs constitutional sxs of DM
gottron papules, Heliotrope eruption; facial erythema; poikiloderma at Shawl/V neck/Holster sign; nailfold abnlities vs slow progressive prox muscle weakness vs interstitial lung dz, dysphagia, heart, polyarthritis/joints
DM subtypes: Clinically amyopathic DM vs juvenile DM vs malig-assoc DM
no skin sxs vs <18yo vs adenocarcinoma to cvx, lung, ovaries, pancreas, bladder, stomach; Myositis-specific ag = highly expressed in ca tissue –> immune rxns against ca cross-react w/ skel muscle fibers –> myositis
DM ab: antiMi2 vs antiJo1 vs antip155/140
against DNA helicase; exclusive in DM vs against histidyl tRNA synthetase; more common in PM vs against transcpxn factor for cellular differentiation; more common in malig associated DM
PM affects? Perforin pathway. any perifascicular atrophy of infiltrates?
skin. Perforin and granzyme granules of CD8 cells = directed towards healthy muscle fibers w/ MHC I –> necrosis. no b/c not DM
PM muscle vs constitutional sxs
Symmetrical, proximal muscle weakness in UE and LE; Facial and ocular muscles not affected vs Lung, heart, oropharynx, joints
PM subtypes: juvenile PM vs malig assoc PM
<18yo vs Colorectal, lung, hepatic ca
PM labs: ANA vs Anti Jo1 ab vs Anti-signal recognition particle (SRP) ab
nonspecific for inflamm or autoimmune vs against histidyl tRNA synthetase vs targets cytosolic protein-RNA complex that couples synthesis of nascent proteins to their proper membrane localization
how to tx PM?
glucocorticoid
Inclusion body myositis affects? Hallmark?
muscles. rimmed autophagic vacuoles containing protein aggregates like in degen dzs –> degen theory of s-IBM
proteins found in IBM
intracellular amyloid that’s immunoreactive to β-amyloid protein; phosphorylated tau, α-synuclein, ubiquitin, presenilin
IBM sxs
Asymmetrical slow progressive weakness of distal and proximal muscles
* Weak quads, finger dexterity, and grip strength
* Atrophy of quads and forearm flexors
IBM labs: high CK vs Anti-cytosolic 5’-nucleotidase (cN1A) ab
blank vs colocalize w/ granular intravacuole deposits and vacuole rims
* Exclusive in inclusion-body myositis
how to tx IBM?
glucocorticoids, wheelchair by 10yo
IBM has autoimmune pathogenesis by?
CD8 cell, B cell, anti-cN1A ab
What is immune-mediated necrotizing myopathy? any CD8 cells (PM/IBM) or perifascicular atrophy (DM) involved?
muscle fiber degeneration, necrosis, regeneration. no
IMNM skin vs muscle vs constitutional sxs
gottron, heliotrope, V sign vs prox muscle weakness vs interstitial lung dz, unknown malig risk
how to dx IMNM?
muscle bx: more necrosis, less inflamm/phag but macs can be seen around necrotic fibers
IMNM labs: High CK; Nml or high ESR, CRP vs Anti-SRP ab vs Anti-HMGCR ab
self explanatory vs triggered by VZV, HPV; targets cytosolic protein-RNA complex that couples synthesis of nascent proteins to their proper membrane localization vs Triggered by statins
how to tx IMNM?
Corticosteroids w/ methotrexate; mortality rte 2-3x higher than gen pop
metabolic myopathies
auto rec d/o leading to insufficient energy prod d/t defect of glycogen, lipid, or mito metab
Disorders of glycogen metab
mutations in genes encoding proteins for glycogen synthesis or degradation –> glycogen can accumulate in tissue
GSD Type II/Pompe dz
Mutation in GAA gene encoding acid α-glycosidase (lysosome) deficiency –> glycogen accumulates in lysosomes of skel or cardiac muscle cells –> enlarged lysosomes –> compressed cell organelles –> injure and replace muscle fibers –> dec cardiac and muscle fxn
Pompe dz clinical pres: infant onset vs late onset
1-5% of residual α-glycosidase activity; cardiomegaly, resp distress, muscle weakness, failure to thrive vs 15-40% of residual α-glycosidase activity; no cardiomegaly, resp fail d/t diaphragm, muscle weakness in limb girdle distribution (prox muscle most affected)
pathology of Pompe dz: light vs e- microscopy
vacuolar myopathy that stain pos for glycogen w/ PAS stain vs see glycogen in enlarged lysosomes –> injured muscle fibers
how to dx vs tx Pompe dz?
Measuring GAA enzyme activity in cultured skin fibroblasts or peripheral blood lymphocytes, high CK vs enzyme replacement therapy
GSD Type V/McArdle dz
Mutation in PYGM gene encoding myophosphorylase –> deficiency –> subsarcolemmal deposits of excess glycogen in periphery of fibers –> dec ATP b/c no glycogenolysis –> inc inorganic phosphate Pi in skel muscle –> inhibit ion pumps –> dec cellular integrity, muscle fiber dmg, rhabdomyolysis
McArdle dz clinical pres
- Exer intolerance in 1st decade of life
- Fatigue, severe muscle cramps relieved by rest
- Muscle contracture –> rhabdomyolysis
- Myoglobinuria –> acute renal failure requiring dialysis
- Second wind phenomenon = sxs subside d/t switch to alternative extramuscular fuel substrates for muscle metab
how to dx McArdle dz?
genetic test of PGYM gene; o Biochemical assay of myophosphorylase activity if genetic test unclear; Forearm exer test (flat lactate curve); high CK, myoglobinuria
how to tx McArdle dz?
no specific tx –> aerobic conditioning, high carb diet
disorders of lipid metabl
Carnitine palmitoyltransferase II deficiency: auto rec mutation of CPT2 gene –> deficiency –> dec mito beta-oxidation of long chain FA –> dec acetyl CoA synthesis –> insufficient energy output in liver, skel muscle, heart –> steatosis in liver, skel muscle, heart, renal tube epithelium; lipid accumulation in skel muscle; life-threatening cardiac arrhythmia
d/o of lipid metab clinical pres: myopathic vs severe infantile vs neonatal
most common and benign; 6-20yo, myoglobinuria by prolonged exer, High CK, No acute muscle or liver dysfunction vs 6mo-2yo; Liver failure w/ hypoketotic hypoglycemia, Cardiomyopathy and peripheral myopathy vs * Days after birth; Liver failure w/ hypoketotic hypoglycemia, Cardiomyopathy, Sz, Congenital anomalies
mito myopathies
muscle weakness and fatigue d/t defect in mito or in resp chain
what does resp chain consist of?
o 5 multimeric complexes in inner mito membrane
o 2 small e- carriers (CoQ10, cytochrome c)
describe mtDNA
small circular 2x stranded molec encoding 13 proteins of resp chain and RNA machinery for translation; High rate of spont mutations, Lack NER mechanism to repair mutations, maternal inheritance
Chronic progressive external ophthalmoplegia
slow progressive paralysis of extraocular and eyelid muscles
which 3 mutations are found in external ophthalmoplegia?
o Auto dom mutation in TWNK and SLC25A4 genes
o Auto dom or rec mutation in POLG and RRM2B genes
o Mito point mutation in MTTL1 gene
external ophthalmoplegia clinical pres
bil ptosis, limited eye movements, face/neck flexors, sometimes limb and bulbar muscle movement, sensorineural hearing loss
how to dx external ophthalmoplegia (3)?
DNA analysis of gene mutations in mtDNA (large deletion) and nDNA; High CK, blood lactate, alanine, Abnl urine organic acid; US/CT/MRI shows thin extraocular muscles
Kearns-Sayre syndrome
multisystem d/o of progressive external ophthalmoplegia, cardiac conduction block and retinitis pigmentosa; more severe than CPEO
what is cardiac conduction block vs retinitis pigmentosa of Kearns-Sayre syndrome?
d/t distal His bundle and bundle branches losing myofibrils and excess mito –> cardiac death vs Retinitis pigmentosa = progressive degen of rod photoreceptor cells in retina –> severe vision impairment
Infectious arthritis/septic arthritis/suppurative arthritis/purulent arthritis
synovial inflammation d/t invasion of joint space by microorganisms
gram pos vs neg pathogens causing nongono arthritis
Staph aureus and Streptococcus (pyogenes > pneumoniae) vs H. influenzae, E. coli, Pseudomonas aeruginosa (IVDU), Salmonella (sickle cell)
risk factors of nongono arthritis
o Large > small joints, males > females, children > adults
causes of nongono arthritis (4)
- Hematogenous spread into synovial capillaries
- Spread from contiguous infected foci like epiphyseal osteomyelitis
- Spread from neighboring soft-tissue infxn
- Direction inoculation of bacteria thru arthrocentesis, corticosteroid injection, arthroscopy
does synovial tissue have basement membrane?
no –> microorgs can access synovial fluid easily –> inflamm and joint effusion –> release TNF alpha, IL1/6/8, neu/macs –> dmg synovium & cartilage –> abscess
nongono arthritis clinical pres
Fever, intense joint pin, malaise in 1-2 wk period
Joint = erythematous, warm, swollen, effusion, dec ROM
Avascular necrosis of femoral head
how to dx nongono arthritis (4)
Gram stain of synovial fluid
PCR for neg cx
US shows joint effusions, XR shows joint space narrowing, MRI shows joint effusion w/ bone marrow edema, cartilage destruction
Synovial fluid count >50k cells, low glu
cause of gono arthritis
o By hematogenous spread of gram neg diplococci N. gonorrheae –> disseminated gonococcal infxn
gono arthritis virulence factors
- Porin B isoform 1A
- AHU auxotype strains
- Strains w/ unique genetic islands
- Strains that don’t express Opa proteins
- Strains that express pili w/ polyG tract
2 major clinical syndromes of gono arthritis
tenosynovitis (inflmm of tendon sheath), dermatitis, polyarthralgia. purulent arthritis (mono or oligoarthritis w/ pain, erythema, dec ROM in 1+ joints)
how to dx gono arthritis?
blood cx shows N. gonorrheae, mild leukocytosis and ESR
bacteria causing acute vs chronic arthritis
pyogenic bacteria, viruses vs Mycobacterium tuberculosis, non-Candida fungi, spirochetes
Tuberculous spondylitis/Pott dz
involves vertebral body or intervertebral discs by TB, usually thoracic or lumbar; no destruction b/c no proteolytic enzymes
how does thoracic vs lumbar present in Pott dz?
- Cold abscess starts as fusiform or bulbous paraspinal swelling
vs - Cold abscess starts as groin swelling and descend below inguinal ligament to medial thigh
Pott dz clinical pres (4)
Insidious onset and slow progression
Pain and tenderness at site
Tuberculous/cold abscess
Spinal deformity (Gibbus deformity = kyphosis w/ sharp angulation d/t slow collapse of 1+ vertebral bodies –> cord compression)
Pott dz labs
High ESR and CP, leuk count nml
TB arthritis. clinical pres vs labs
monoarthritis usually in hip or knee. Joint pain, No fever or systemic sxs, Phemister triad: periarticular osteoporosis, peripherally located osseous erosion, gradual joint space narrowing vs High leuk count, low glu, Pos cx, Caseous granulomas
Lyme arthritis/Lyme dz
Borrelia (B. burgdorferi from Ixodes ticks in America, B. afzelli and garinii in Europe)
early local vs early dissem vs late dissem vs PTLDS
erythema migrans (red nonitchy painless macule) –> can tx w/ abx vs EM, AV heart block, fever, facial nerve neuritis w/ facial nerve palsy, acute septic meningitis w/ stiff neck vs Monoarticular arthritis in large joints –> warm effused joints; Pannus development like in RA; Synovial fluid shows high leuk count, no live B. burgdorferi vs Fever, difficulty sleeping, arthralgia, myalgia, memory impairment, HA; can range from mild to severe
how to dx lyme arthritis/dz?
ELISA –> igM western blot
viral arthritis example: direct invasion of joint space by Chikungunya
- Chikungunya virus = arthropod alphavirus transmitted to human by infected Aedes mosquitoes
o Chikungunya fever = triad of acute febrile illness, severe symmetrical polyarthralgia/arthritis, maculopapular rash
viral arthritis example: immune complex formation by parvovirus 19
- Parvovirus B19 = transmitted to humans by aerosolized infected respiratory droplets
o Erythema infectiosum = self-limited febrile rash-producing dz
Biphasic but no joint destruction: Fever and nonspecific flu-like sxs; Erythematous malar/slapped cheek rash and Acute onset symmetric polyarthritis Involveing small joints of hands and wrists
(Has detectable antiviral ab)
Sxs resolve in 3wks
viruses that spread hematogenously to form immune complexes –> arthritis?
- Parvovirus B19, HepB/C, Rubella, measles/mumps, HIV1, HTLV1
how to dx viral arthritis?
o IgM serologic testing then IgG serologic testing
o Isolation of virus from synovium
Rheumatoid arthritis
chronic, immune mediated, systemic inflammatory dz involving synovial joints
RA clinical presentation
slow gradual onset;
PIP, MCP, wrist, elbow, shoulder
MTP, ankle, knee
Hip, cervical spine, temporomandibular
Swelling, pain, warmth, dec ROM
RA deformities: ulnar deviation of fingers vs Swan neck deformity vs Boutonniere deformity
blank vs Hyperextension of PIP and flexion of DIP d/t laxity of PIP vs Hyperextension of MCP, hyperflexion of PIP, hyperextension of DIP
RA: skin vs heart vs vasculitis
- Palpable subq nodule/rheumatoid nodule
- Vasculitic lesion –> palpable purpura, skin ulcer, digital infarct
vs - Rheumatoid nodules in epicardium, myocardium, valves –> valve dz and heart block
- Angina, MI
vs - Necrotizing vasculitis of small and medium vessels in diff viscera
- Skin, finger, peripheral nerves
RA: lungs vs eyes vs kidney vs Felty syndrome
Rheumatoid nodules in lungs –> Pleural effusion, interstitial lung fibrosis vs Keratoconjunctivitis sicca, Epi/scleritis vs Systemic AA amyloidosis vs triad of seropos RA, neutropenia, splenomegaly
how to dx RA?
o Inflamm arthritis involving 3+ joints, symmetric involvement of MCP and PIP, pos RF and/or anti-CCP, high ESR or CRP, sxs last 6+ wks
How are you “seroneg RA”? is RF specific?
o Pts w/ neg RF and anti-CCP but pos for all others. no –> SLE, scleroderma, Sjorgen, infxn
RA labs: acute phase vs hematologic vs autoimmune ab vs synovial fluid
high ESR, CRP, RA vs anemia, mild leukocytosis vs RF, antiCCP, ANA vs sl cloudy, yellow, no cx
RA imging
joint space narrowing b/c articular cartilage destruction, bone erosion –> irreversible dmg
how to tx RA?
NSAIDS, DMARDS, corticosteroids, immunosuppressants
juvenile idiopathic arthritis
all forms of arthritis <16yo, persists 6+ wks, unknown cause
JIA: oligoarticular vs polyarticular vs undifferentiated
</= 4 joints during 1st 6mo of dz
LE, no small joints
RF neg, ANA pos
vs
>/= 5 joints
Symmetric involvement of fingers, wrists, knees, ankles
RF neg –> better prognosis, RF pos –> similar to adult RA
ANA pos
vs
Don’t meet criteria of one or meet mult criteria of each
JIA: Enthesitis-related arthritis vs psoriatic vs systemic/Still dz
Joints and entheses (insertions of tendons and ligaments)
* Achilles tendon
* Ankylosing spondylitis, reactive arthritis
RF and ANA neg
vs
Polyarthritis w/ psoriasis, dactylitis/SI-itis/enthesitis, DIP, nails, conjunctivitis/uveitis, aortic regurg
RF neg
vs
Fever, macular skin rash, lymphadenopathy, hepatosplenomegaly, serositis
RF and ANA neg
JIA labs. how to tx JIA?
High ESR; RF, ANA, HLA-B27 distinguish types. Tx same as RA
ganglion cyst vs synovial cyst vs Baker’s/popliteal cyst
pseudocyst of dense fibrous connective tissue w/ gelatinous fluid, hyaluronic acid, mucopolysacch, and w/o synovial cells vs true cyst w/ synovial fluid and synovial cells; can coexist w/ OA, RA, meniscus tears vs most common type of synovial cyst in popliteal fossa d/t distention of gastrocnemius
tenosynovial giant cell tumor
benign locally aggressive tumors of joints, bursae, tendon sheaths; t(1;2)(p13;q37); mutation –> upreg CSF1 gene –> inc monocyte colony-stimulating factor 1 –> inc macs
localized vs diffuse/pigmented villonodular synovitis
both pain, swelling, dec ROM. red/brown nodules of Mononuclear cells/neoplastic synoviocytes, histiocytes, osteoclast-like multinucleated giant cell, lipid-laden macs; Surrounded by thin fibrous capsule; Thumb, index and middle finger vs Red-brown mass over hyperplastic synovium with villonodular growth pattern –> covers entire synovial membrane; knee > hip > ankle > shoulder > elbow
soft tissue tumors
from pluripotent mesenchymal stem cells residing in soft tissues
lipoma
t(3;12)(q27-28;q13-14) –> fusing HMGA2 gene w/ LPP gene; Yellow doughy tumors made of mature univacuolated adipocytes w/ minimal variation in size; Superficial lipomas in subq tissue > deep lipomas in muscle > visceral lipomas in resp tract, GI tract, intracranial space
liposarcoma: well diff vs myxoid vs pleomorphic
Amplification of chrm12 q13-q15 –> inc MDM2 gene –> neg regulator of P53 vs * Translocation t(12;16)(q13;p11) –>FUS-CHOP gene fusion –> blocks differentiation of adipocyte precursors –> immature adipocytes in continuous cycle of prolif w/o differentiation vs complex chrm abnormalities. Thigh > limb girdle > upper limb > retroperitoneum
tumors of fibrous tissue: look at study guide
yep
tumors of skel muscle: rhabdomyosarcoma
in children
Soft tissue sarcoma w/ skel muscle differentiation
Loss of heterozygosity of chrm 11p15 –> inc IGF-2 gene –> inc growth of RMS cells
rhabdomyosarcoma: embryonal vs alveolar vs pleomorphic vs spindle cell
- Densely packed hypercellular areas of small undifferentiated cells alt w/ hypocellular myxoid areas
- GU, head, neck
vs - Primitive round cells forming conglomerates similar looking to lung alveoli
- Extremities, trunk, perianal
vs - Large, atypical, multinucleated polygonal eosinophilic cells
- Extremities, trunk
vs - Fascicles of spindle cells embedded in collagen stroma
- Paratesticular
tumors of smooth muscle: look at study guide
yep
tumors of uncertain histogenesis: synovial sarcoma vs undifferentiated pleomorphic sarcoma
NOT from synovial membrane –> from multipotent stem cells capable of differentiating to mono/biphasic mesenchymal spindle and/or epithelial cuboid cells (cuboid cell = PAS pos)
t(X;18)(p11.2;q11.2) –> fusion of SS18 gene and SSX gene –> large mass in deep soft tissue
vs
* Storiform = plump spindle cells arrange in short fascicles in cartwheel pattern
* Pleomorphic pattern = plumper fibroblastic cells and rounded histiocyte-like cells
osteoid osteoma & osteoblastoma. XR shows?
Translocation of FOS oncogene encoding transcpxn factor –> overexpression of FOS protein in osteoblasts –> dull achy pain. small round central radiolucency (central nidus) made of osteoid trabeculae w/ peripheral sclerotic dense bone
osteosarcoma
most common malig tumor from osteoid or immature bone made by tumor cells; * Loss of fxn mutation in RB gene encoding retinoblastoma protein or loss of fxn mutation in TP53 gene encoding p53 protein –> inactivate CDKN2A gene encoding tumor suppressors p16 & p14, AND overexpressing MDM2 gene inhibiting p53
how does osteosarcoma spread? imging shows?
Spreads via bloodstream to lungs. Mixed osteoblastic or sclerosing (radiodense) and osteolytic (radiolucent) lesion; Codman’s triangle: bone cortex = destroyed –> tumor extends to soft tissue –> lifts periosteum –> periosteum ossifies –> triangle area
risk factors of osteosarcoma
o Prior radiation or chemotherapy (alkylating agents)
o Paget’s
o Fibrous dysplasia
o Genetics (Li Fraumeni’s)
osteochondroma/exostosis
most common benign tumor of cartilage-covered bone; Loss of fxn mutation in EXT1 gene encoding enzymes that synthesize heparin sulfate glycosaminoglycans
osteochondroma/exostosis consists of? where does it usually occur? what does img show?
2 components: Continuous extension cortex and Cartilage cap:
Nml chondrocytes in lacunae in chondroid matrix
Outer part of cap has periosteum off underlying bone
Inner part of cap has stalk made of mature bone.
* Painless palpable mass in metaphyseal regions of long tubular bones
o Knees > humerus.
bony protrusion
chondroma. img shows?
benign slow growing cartilaginous tumor, can become chondrosarcoma; Mutation in isocitrate dehydrogenase 1&2 (IDH1&2) genes; Oval, central lucent lesion w/ or w/o matrix calcifications
periosteal vs endosteal chondroma
From surface of periosteum and grows exophytically
Long tubular bones –> palpable swelling
vs
From medullary cavity and grows expansively
Small bones in hands and feet –> bulbous swelling –> pathologic fx
Ollier dz and Maffucci Syndrome = nonhereditary dz from enchondromatosis
chondrosarcoma
malig cartilaginous tumor (low to intermediate/grade 1-2); second most common malig bone tumor; * Mutation in isocitrate dehydrogenase 1&2 (IDH1&2) genes
chondrosarcoma pathology vs radiology
o Gross: large lobulated mass w/ light blue color in any bone
o Micro: neoplastic cells producing hyaline cartilaginous matrix
vs
o Radiolucency
o Cortical destruction or soft tissue mass
EWS
3rd most common malig bone tumor; t(11;22)(q24;q12) –> EWS/FLI1 fusion –> dom oncogene –> stimulate cell prolif; Strong CD99 staining
EWS imging
o Periosteum = lamellated onion skin appearance
o “Sunburst” pattern
o “Hair-on-end” pattern
giant cell tumor of bone
benign locally aggressive tumor w/ multinucleated osteoclast-like giant cells; Dark brown soft mass d/t hemorrhage or necrosis –> pain, swelling, dec ROM
3 cell types of giant cell tumor of bone. imging?
o Mononuclear spindle-shaped cells; Mutation in H3 histone family member 3A (H3F3A) gene encoding histone 3 protein
o Multinucleated giant cells
o Mononuclear histiocytic cells
o img: Lytic lesion in epiphysis and involving metaphysis w/ thin shell
aneurysmal bone cyst
benign locally aggressive tumor w/ anastomotic cavities containing blood; t(16;17)(q22;q13) in osteoblast cadherin gene CDH11 and USP6 gene –> inc NFkB –> inc matrix metalloprotease –> cystic bone resorption
what are Anastomosing channels lined by in aneurysmal bone cysts? img?
endothelial cells and have no elastic lamina or muscular layers like true blood vessels. o Sharply defined expansile osteolytic lesion w/ thin sclerotic margins
most common sites for bone metastases
- Vertebral body = most common site for metastatic deposit in vertebrae b/c has red bone marrow
- Skeleton = 3rd most common site for metastases following lung and liver
3 types of bone metastases: osteolytic vs osteoblastic vs mixed
destruction of nml bone by osteoclasts d/t IL1/6/8/11 and TNFα vs making new bone vs having 2+ types of bone metastases in a single pt
bone metastases clinical pres vs lab
o Bone pain
o Bone destruction d/t osteolytic metastases –> hypercalcemia
o Spinal cord compress
vs
o High ALP
fibromatosis
- Fibroblast prolif
- Infiltrative growth
- Variable amt of collagen in b/w prolif cells
- Lack of cytological features of malignancy
- Aggressive clinical behavior
superficial fibromatosis: palmar vs plantar vs penile
Duypuytren’s contracture vs Lederhose dz; nodule in central and medial plantar aponeurosis vs Peyronies; Tunica albuguinea of corpus cavernosum –> abnl penile curvature
what causes superficial fibromatosis?
- Immunostaining β-catenin = component of WNT
what causes sporadic vs familial desmoid tumor?
Mutation in CTNNB1 gene encoding β-catenin –> no β-catenin degradation –> inc β-catenin –> inc WNT pathway –> cell prolif vs Mutation in APC gene –> no β-catenin degradation –> inc β-catenin –> inc WNT pathway –> cell prolif
