New Flashcards
1
Q
HIV life cycle
A
Morphology
- nucelocapsid core
- > contains viral RNA
- > reverse transcriptase
- > integrase
- envelope
- > lipid membrane
- > gp120
- > gp41
Binding to target cell
- gp120 binds to CD4 on dendritic cells
- > anogenital mucosa
- > cervicovaginal, tonsillar and adenoidal tissue
- cell to cell spread
- > macrophages
- > CD4 lymphocytes
- tropism determined by co-receptors on host cell
- > CCR5 for macrophage tropic
- > CXCR4 for T cell tropic
Cell entry
- conformational change in gp120 with binding to CD4
- > facilitates binding to co-receptors
- > brings gp41 forward to penetrate cell membrane
- > gp41 then coils into hairpin and brings virion and target cell together
- fusion of virion and target cell
- > uncoating of capsid and entry and preintegration complex
Viral replication
- on route to nucleus
- > RNA reverse transcriptase catalyses reverse transcription of genomic RNA
- > double stranded proviral DNA
- transported into nucleus
- integrase
- > incorporates proviral DNA into host genome
- cellular activation or latency
- transcription of HIV gene
- > mRNA translated into viral proteins
Viral spread
- assembly of genomic RNA, viral proteins and enzymes
- budding through lipid bilayer
- > gives virus its envelope
- protease
- > cuts long HIV polyprotein chains into smaller functional proteins
- > makes mature virus
2
Q
HIV pathophys
A
Acute infection
- hours
- > proliferation within lymphoid cell within mucosa
- > occurs more rapidly in lymphoid organ such spleen with IV exposure
- days to weeks
- > dispersion to draining lymph nodes and GALT
- > rapid proliferation and burst of viraemia
- > infection firmly established lymphoid tissue
- acute HIV syndrome
- > 2-4 weeks
- > infective mononucleosis syndrome
- > associated with seroconversion
Immune response (following viraemia burst)
- humoral
- > antibodies within 3 months of infection
- cell mediated
- > CD4 helper cells
- > cytotoxic T cells
- > NK cells
Immune evasion
- rapid mutation
- > renders antibodies ineffective
- sequestration in immunologically privileged sites
- > brain
- > germinal centers in lymph nodes
- down regulation of HLA class 1 molecules
- > prevents recognition and destruction by cytotoxic and CD8 T cells
- > immune exhaustion
- > up-regulation of immune checkpoint receptors
- > qualitative decline in CD8 T cell function
- establishment of viral reserve
- > pool of latently infected, resting CD4 T cells
- > not eradicated by current therapy
Establishment of set point
- level of viraemia established by 6 months
- correlates with slope of disease progression in untreated patient
CD4 cell depletion
- lymphocyte turnover is a key feature of HIV
- > seen in both CD4 and CD8 T cells
- CD4 decline compared to CD8 due to
- > loss of plasma membrane integrity with viral budding
- > interference with cellular functions due to viral infection
- > apoptosis
- > pryoptosis
- > cell mediated and humoral autoimmunity
- > impaired lymphopoeisis from reduced survival cytokines and alteration in lymphoid tissue integrity
Chronic HIV
- after seroconversion and set point
- until CD4 count <200 or AIDS illness
- > median =8-10 years
- gradual decline in CD4 cells
- asymptomatic most common
- symptomatic
- > persistant generalised lymphadenopathy
- > vulvovaginal and oropharyngeal fungal infections
- > bacterial folliculitis
- > seborrheic dermatitis (erythema and scale on face)
- > increased incidence of common illnesses including STI’s and strep pneumoniae
3
Q
HIV modes of transmission
A
parenteral
- blood transfusion highest risk
- > approx 0.9 RR
- needle sharing
- needle stick
- > 20 per 10,100
sexual (blood and sexual fluids)
- most common route, but ineffective
- worst = receptive anal
- insertive anal
- insertive and receptive penile-vaginal
- receptive and insertive oral
- > low risk
vertical transmission
- during pregnancy
- during delivery
- during breastfeeding
other body fluids
-spitting, biting, saliva etc = neglible
4
Q
HIV ddx
A
MR HIV SANG (crocodile rock)
- Mononucleosis
- > EBV
- > CMV
- Rubella
- Hepatitis (viral)
- Influenza
- Viral infections (serum sickness like syndrome)
- Syphilis
- Autoimmune
- > SLE
- Neoplasia
- > lymphoma
- Gonococcal disseminated infection
5
Q
HIV testing
A
fourth generation antigen/antibody tests
- first line screen in Aus
- positive within 2-6 weeks
- ELISA antibody and p24 antigen
confirmation
- with western blot
- > serum electrophoresis
- > incubated with antibodies and washed
- > bands observed on film
- negative result
- > western blot develops slower than screening test
- > repeat in 1-2 weeks
rapid point of care
- antigen/antibody
- approx 20 mins
- sensitivity and specificity >99% when combined with western blot
other
- fourth generation ELISA
- > IgG detection
- > window period =2-4 weeks
- p24 antigen
- > core protein
- > present during viral replication
- > acute infection and late stages
- > becomes positive after HIV viral load
- viral load
- > RT PCR
- > ultrasensitive: 20 RNA copies/mL
- > blood or other fluid
- > most sensitive during window period
- nucleic acid testing
- > mainly for neonatal infection
6
Q
HIV investigations
A
glucose
urinalysis
-treatment implications
FBC -differential -film EUC -eGFR for treatment LFT -treatment -hepatitis comorbid Heterophile antibody ->can be positive in HIV ->utility questionable
confirm HIV
- fourth generation antigen/antibody test
- > confirm with western blot
disease status
- viral load
- CD4 count and percentage
- > normal for HIV = 800
- > above 500 = asympto
- > below 350 = sympto
treatment selection
- genomic resistance testing
- HLAB-5701
- > hypersensitivity to abacavir
comorbidities
- STI
- > PCR gon/chlam
- > syphilis serology
- hepatitis
- > IgG anti-HAV
- > HBV-sAg + HBV-sAb + HBVcAb
- > HCV antibody
- TB
- > skin test
- herpes
- > VCZ + HSV IgG
- toxoplasmosis IgG
- beta HCG
CXR for infective symptoms
7
Q
HIV treatment
A
pre-exposure prophylaxis
- high risk
- recommended
- medium risk
- > consider
- emtricitabine + tenofovir
antiretroviral treatment options
- > nucleotide/nucleoside reverse transcriptase inhibitors
- > non nucleoside reverse transcriptase inhibitors
- > protease inhibitors
- > fusion inhibitors
- > entry inhibitors
- > integrase strand transfer inhibitor
before starting antiretroviral treatment
- consider IRIS
- > immune reconstitution inflammatory syndrome
- > inflamm reaction to latent infection (eg. mycobacterium avium)
Principles of treatment
- at least three drugs are required for initial therapy
- first line
- > two nucleotide/nucleoside RTI + integrase strand transfer inhibitor
- > eg. emtricitabine + tenofovir + dolutegravir
- > combination single tables daily improve adherence
- can be reduced to two drugs once viral load suppressed
Interactions
- most protease inhibitors given with boosting drugs
- > boosting drugs inhibit CYP450
- > CYP450 metabolises antiretroviral drugs
- non nucleoside RTI are also commonly involved
- integrase strand inhibitors
- > PPIs limit absorption
8
Q
complications breast cancer treatment
A
breast/chest wall
- fat necrosis
- radiation induced fibrosis
musculoskeletal
- reduced arm mobility
- lymphoedema of upper limb
- osteoporosis, mylagias/arthralgias with aromitase inhibitors
neurologic
-neuopathies from surgery or chemo
cardiovascular
-radiation and chemo associated with cardiovascular events and cardiomyopathy
tumours
- radiation
- > myeloid
- > oesophageal
- chemo
- > myeloid cancer
- > myelodysplasia
infertility
cognitive impairement
fatigue
anxiety and depression
9
Q
ddx hoarseness
A
Pray Its Not Malignant Laryngeal Cancer
- polypoid corditis
- > oedema of vocal cords
- > chronic irritation eg smoking
- Inflammation (smoking, GORD etc)
- > polyps
- > nodules
- Neuro
- > stroke (lateral medullary)
- > parkinsons/MG/MND
- > recurrent laryngeal nerve (lung cancer)
- Muscle tension dysphonia
- > dysfunction of muscle contraction
- Laryngitis
- > acute
- > chronic
- Cancer
10
Q
osteoporosis pathophys
A
remodelling
- function
- > repair microdamage
- > maintain calcium homeostasis
- normally a balance
- > osteoclast formation of resorption pit
- > osteoblast synthesis of bone matrix followed by mineralisation
Regulation
- > estrogens and androgens
- > PTH, calcitonin and calcitriol
- > local growth factors and cytokines
- > nutrition
- > physical activity level
Signalling between osteoclasts/blasts
- > RANKL secreted by osteocytes and osteoblasts
- > RANK activates osteoclast
- > osteoprotegrin is decoy for RANKL secreted by osteoblasts
- > Wnt pathway activates osteoblasts and decreases RANKL
Imbalance
- peak bone mass at 20
- after middle age imbalance with resorption predominating
- exaggerated by risk factors
- exaggerated with onset of menopause
- > marrow and bone cells express ER
- > loss of estrogen increases RANKL and decreases OPG
- > also reduced osteoblast lifespan and increased for osteoclasts
overall
- systemic skeletal disease
- characterised by
- > low bone mass
- > abnormal bone architecture
- leading to
- > bone fragility
- > increased risk of fracture
11
Q
osteoporosis risk factors
A
non modifiable
- family hx
- female
- age
- prior fracture
- menopause
- hypogonadism
modifiable
- smoking
- alcohol
- low BMI
- immobilisation
- calcium intake
- vitamin d deficiency
- drugs
- > glucocorticoids
12
Q
diseases associated osteoporosis
A
NIGGER
- neoplasia
- > MM
- inherited disorders
- > marfans
- gonadal (hypo)
- > Turners
- gastrointestinal
- > cirrhosis
- endocrine
- > cushings
- > diabetes
- rheumatological
- > RA
13
Q
hx and exam osteoporosis
A
Hx
- risk factors
- previous falls
- previous fractures
- meds
- > glucocorticoids
- > aromitase inhibitors
- pain
- change in height (kyphosis)
- > 3cm or more
- diet
- ADLs
- home set up (falls risk)
Exam
- height, weight, BMI
- observe kyphosis
- any tenderness
- falls risk
- > vision
- > balance
- > gait
- > lower limb strength/sensation
14
Q
ddx osteoporosis
A
MOM CAP
- mets to bone
- osteomalacia
- MM
- CKD
- adenoma (pituitary = primary PTH)
- pagets
for KOF
- acetabular
- pelvic
- shaft
- femoral head
15
Q
investigations osteoporosis
A
FBC -film ->MM EUC -CKD -eGFR for drug therapy LFT -al phos CMP -calcium -phosphate PTH Vit D
X-ray
- of fracture
- demonstrate osteoporosis/penia
DXA
- total hip best
- lumbar spine
- femoral neck
Quantitative ultrasound of heel
- if DXA unavailable
- predictive for hip fractures
consider
- serum/urine PEP
- > MM
- urine free cortisol
- > elevated in cushings
- testosterone in men
