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Pathology block 2
Terms in this set (682)
Mendelian disorders characteristics/examples of codominance
result from mutations in single genes with large effects
- dominant or recessive
- co-dominance: blood groups; both alleles contribute to phenotype
What are characteristics of autosomal dominance?
uta- manifested in heterozygous state
- defect in every generation
- delayed onset
- reduced penetrance and variable expressivity
What is mutated in autosomal dominant disorders?
regulatory proteins and structural proteins
- inheritance pattern
- chromosome affected
CT disorder primarily in changes of skeleton, eye, and cardiovascular system
- defect in fibrillin (FBN1) major component of ECF
- chromosome 15q21
Skeletal abnormalities in patients with Marfan Syndrome
tall, thin habitus with long extremities
Dolichocephaly (head long and thin)
restrictive lung disease (chest wall/rib problems)
Ocular and Cardiovascular changes in patient with Marfan
ocular - lens is fine, retinal detachment
CV - mitral valve prolapse (CT weak, pushes valve into LA)
What disease is associated with the following presentations?
heterogenous group of disorder that result from defect in collagen synthesis/structure
skin: hyper-extensible, fragile, easy bruising, very stretchy
Classic form (type I/II) Ehlers-Danlos Syndrome:
mutation in the genes for Type V collagen (COL5A1 and COL5A2)
Kyphoscoliosis EDS (type VI)
- common inheritance
- mutation in the gene encoding lysyl hydroxylase
eyes: rupture of cornea and retinal detachment (like Marfan)
most common autosomal recessive form of EDS (exception)
body habitus more normal (unlike Marfan stature)
neurofibromas; benign tumors
Type I Neurofibromatosis 3 major features:
1. multiple neural tumors (neurofibroma)
2. pigmented nodules of the iris (Lisch nodules)
3. cutaneous hyper-pigmented macules (cafe au lait spots)
Presentations and chromosome affected in Type I neurofibromatosis
NF1 tumor suppressor gene (17q11.2)
associated with skeletal lesions and other tumors such as malignant peripheral nerve sheath tumors, gliomas of the optic nerve, other glial hamaratomatous lesions, and pheochromocytoma
Type 2 Acoustic Neurofibromatosis
- gene associated
- patient complaints
associated with bilateral acoustic schwannomas and multiple meningiomas
cranial nerve 8 (acoustic)
gene: NF2- tumor suppressor gene
disease of the two's (type 2, only 2/3 presentation, 2 sides affected, on chromosome 22)
tinnitus bilateral / vertigo
cafe au lait present
von Hippel-Lindau disease
- associated diseases
hemangioblastomas of CNS and cysts of pancreas, liver, kidney (most common in the cerebellum and retina)
VHL gene: tumor suppressor gene on chrom.3
renal cell carcinoma (multiple and bilateral)
What is occurring?
- filled inside of blood vessels
What is pictured?
Hemangioblastomas in cerebellum associated with what presentations
common in children
child with issue balancing since compressing the cerebellum
Hemagioblastoma of retina presentation:
common in adults
seen being filled with blood vessels
adults with visual problems; child has gait problems
- heterozygote presentation vs. homozygotes
LDL receptor gene
- defective LDL transport/ increased synthesis
one of the most frequent mendelian disorders
heterozygotes: 2-3x increase of plasma cholesterol; xanthomas; premature atherosclerosis
homozygotes: 5-6x increase of plasma cholesterol; MI before 20 y/o
Treatment for familial hypercholesterolemia
statins to decrease cholesterol via suppressing intracellular cholesterol synthesis through inhibition of enzyme HMG CoA reductase = increase LDL receptors
Characteristics of autosomal dominant disorders
manifest in homozygous
25% chance sibling affected
uniform expression of defect
onset early in life
What are the likely mutations associated with autosomal dominant disorders?
loss of function of enzyme proteins
lysosomal storage diseases (location is key)
- accumulating substance
mutation in alpha--subunit --> hexosaminidase A deficiency
- Ashkenazi jews
- accumulation of GM2 into various tissues, including CNS
- early age onset ~ 6 months
-ballooning of neurons
Presentation of patients with Tay Sachs Disease:
- Sx and death time frame
ballooning of the neurons with whorled configuration of lysosomes (EM)
motor and mental deterioration (delayed milestones)
cherry red spot on macula
death by 2 to 3 y/o
Neimann-Pick disease type A
severe infantile form with extensive neuro involvement, marked visceral accumulation of sphingomyelin, progressive wasting
death within first 3 years
ft: hepatospenomegaly, generalized lymphadenopathy
Neimann-pick disease type B
- sites affected
- clinical features
organomegaly but no CNS involvement
accumulation of sphingomyelin in RES, CNS, and eye
RES: lipid-laden foamy macrophages in liver, spleen, lymph nodes, bone marrow, etc.
CNS: vacuolation/ballooning of neurons
eye: retinal cherry-spot
death within first or second year
- key to differentiate
- pathological change MOA
deficiency of glucocerebrosidase
- most common lysosomal storage disorder
- European Jews
- accumulation of glucocerebrosides in mononuclear phagocytes (of RES) called Gaucher cells (key)
pathological changes caused by accumulation and activation of macrophages and cytokine secretions (IL-1, IL-6, TNF)
Clinical features seen in an adult with Gaucher (commonly):
splenomegaly, pancytopenia/thrombocytopenia, pathological fractures (osteoporosis)
infant: neurological involvement
prognosis: progressive form is compatible with long life
PAS stain to light up glucocerebrosides in cytoplasm of macrophages
- Gaucher disease
wrinkled tissue paper in cytoplasm
- most associated features
- 2 subtypes
deficient in lysosomal enzymes involved in degradation of GAGs: dermatan sulfate, heparan sulfate, keratan sulfate, chondroitin sulfate
coarse facial features, clouding of the cornea. (worse prognosis)
joint stiffness, mental retardation
seen in mucopolysaccharidoses
- due to GAGs building up in different areas of the face
Graves, hypothyroidism seen too
What are the causes of coarse facial features>
Seen in hurler's --> so Hurler's has a worse prognosis than Hunter
Where is this seen?
- clinical presentation
hepatospenomegaly by 6-24 months, growth retardation
death by 6-10 years
- clinical features
no clouding of the cornea
milder clinical course
"Hunter is old school and uses a cross-bow"
Von Gierke's Disease
deficiency of glucose-6-phosphate
hepatomegaly and hypoglycemia (confused/disoriented)
deficiency of muscle phosphorylase
muscle weakness and cramps after exercise
deficiency of alpha-glucosidase (acid maltase)
cardiomegaly - glycogen builds up and causes restrictive cardiomyopathy -- unable to open well in diastole and fill --> biventricular heart failure
clear vacuoles represent glycogen inside myocardial fibers
- restrictive cardiomyopathy
What is pictured?
Characteristics of X-linked disorders
no male to male transmission
carrier: all daughters of affected males
- female siblings of patient may have mild symptoms
sons of heterozygotes:
- 50% chance of receiving mutant
X-linked dominant --> vitamin-D resistant rickets (female)
If patient has vitamin-D resistant rickets, what occurs when they are treated with vitamin D infusions?
disorders with multifactorial inheritance:
combined action of environmental influences and 2+mutant genes
Ex: hair, eyes, skin, height, intelligence
likely of both identical twins being affected significantly <100%
(normally in twins, there is 100% concordance like in Lupus)
FISH (fluorescent in situ hybridization)
adjunct to karyotyping and cytogenic analysis
exact multiple of haploid number
ex: triploid = 69
chromosome is not an exact multiple of 23
- neoplasia importance - malignancy more aggressive
hyperploidy is better prognosis
one less chromosome via nondisjunction
- cri du chat (5p-)
one extra chromosome
most commonly associated with spontaneous abortion
- clinical features
- incidence related to:
most common chromosomal disorder/cause of mental retardation in U.S.
incidence related to maternal age (35 y/o increased chance)
extra chromosome is of maternla origiin
- flat facial profile
- palpebral fissures
- epicanthic folds
- Simian creases (single palmar crease/ no opposition)
- severe mental retardation
Other diseases associated with Trisomy 21
congenital heart disease - ostium primum, atrial septal. defects (general pop. commonly ostium secondum)
Acute leukemia (ALL/AML)
Hirschbrung disease (congenital megacolon)
Trisomy 18 (Edwards Syndrome)
- clinical features
micrognathia (small mandible)
rocker bottom feet (also in Patau)
congenital heart defects (VSD)
death within 1 year
(child/adult has to be Down syndrome)
Trisomy 13 (Patau Syndrome)
- clinical features
cleft lip and palate
rocker bottom feet
death within 6 months
What is the Lyon hypothesis?
One of females X chromosomes are inactivated by XIST
inactivated X chromosome seen in all cells derived from precursor cell and represented as Barr body
(#X chromosome - 1)
male hypogonadism occurring when there are 2+ X chromosomes and one or more Y chromosomes
47,XXY (have barr body)
tall, thin eunuchoid body habitus (also in Marfan)
small atrophic testes (increased estradiol)
gynecomastia (breast development)
increased plasma FSH and estradiol levels
Barr body present
"big breasteses, small testeses"
- causes what?
- clinical features
complete/partial monosomy of X chromosome (no Barr)
hypogonadism in phenotypic females
most common sex chromosome abnormality in females
webbing of neck
wide set nipples
coarctation of aorta
normal mental status
presence of testicular and ovarian tissue in same individual (extremely rare)
represents a disagreement between phenotypic and gonadal sex
male pseudo-hermaphoditism (most common form)
associated with androgen sensitivity in the male
Single-gene disorders with non-classical inheritance are classified into 4 categories:
triple repeat mutations (Fredrich Ataxia)
Mutations in mitochondrial genes
Fragile X Syndrome
- distinctive feature / clinical presentation
mutation: long repeating sequence of 3 nucleotides on X chromosome mapped to FMR1 gene
2nd most common cause of mental retardation
distinctive: macro-orchidism (large testes)
other features: long face with large mandible, large everted ears
micro-deletion on paternal chromosome 15
mental retardation, obesity, hypogonadism
Angelman (happy puppet) syndrome
UBE3A gene -- maternal chromosome
mental retardation, seizures, ataxia (gives appearance of puppet on string), inappropriate laughter
"all mothers are angels"
What is a hypersensitivity reaction?
- why does is it result?
excess/harmful reaction to antigen that the individual has been previously exposed to
- results from an imbalance between effector mechanisms of immune responses / control mechanisms to control responses
How is type I HSR response described?
What is the defining characteristic of Type II HSR?
Type III hypersensitivity reaction mediated by what?
immune complex mediated
Type IV is a ___ mediated reaction
Type I HSR:
- triggering event
- disorder/reaction that can occur
antigen binding to IgE antibody on surface of mast cells
systemic reaction or local reactino
What is the cause/result of a systemic reaction in a Type I HSR?
follows an injection of antigen into a sensitized individual (bee sting) or following ingestion (peanut)
What molecules can cause anaphylactic shock for the systemic vasodilation?
C5a and C3a
local reactions in HSR I presentations:
- what are the phases?
local cutaneous rash/blisters
1. immediate phase
2. late phase
Immediate reaction in HSR I:
- physiological characteristics
- what mediates these reactions
vasodilation, vascular leakage, glandular secretions
- histamine release by mast cells
Late phase reaction in HSR I:
- physiological characteristics
- what is resulting damage
- what cells are recruited
infiltration of tissues with eosinophils, neutrophils, basophils, CD4 T cells
- leukocytes recruited
tissue damage in the form of mucosal epithelial cell damage
What are most immediate hypersensitivity disorders caused by:
excessive TH2 responses which produce IgE and promote inflammation
When does mast cell activation occur?
after IgE cross linking with antigen
Eosinophils liberate what substances?
proteolytic enzymes -- major basic protein and eosinophilic cationic protein
- damaging tissues
Primary mediator of HSR I reaction:
Secondary mediators of HSR I:
leukotrienes which are responsible for bronchospasms/bronchoconstriction associated with asthma (also by histamine)
Which HSR are represented in the picture?
immediate (erythema) and late phase (edema from vascular permeability)
When a HSR becomes systemic, what happens to the larynx?
- what do you need to do to the patient?
laryngeal edema -> patient needs to be intubated
systemic vasodilation leads to:
- skin warmth (A,S,N shock)
- mediated by:
- Ab association
- classic cell
mediated by cytotoxic antibodies (IgG, IgM)
- antibody binding to antigens on cell surface
classic cell = RBC
Which reactions fall under HSR II?
1. transfusion reaction
2. drugs that bind to RBC (penicillin)
3. hemolytic anemia (SLE)
Steps of a type II HSR:
1. form cytotoxic antibodies
2. antibody binding to antigens on cell surface
3. complement dependent phagocytosis or lysis
4. complement independent (ADCC)
- which HSR
type II HSR
- hemolytic disease of the newborn; lots of erythroblasts being produced by baby in liver and spleen
Autoimmune hemolytic disease
- certain drug reactions
Which HSR is Graves disease?
- what is affected
TSH receptor antibody
- Graves is a result of up-regulation
Which HSR is Myasthenia Gravis?
- what is affected
- Ach receptor antibody
- a result of decreased activity
How can you differentiate Myasthenia Gravis from Lambert Eaton?
MG: muscle weakness, worse through the day
LE: muscle weakness gets better
- Ab to Ca channels at pre-synaptic membrane
Which cancer is associated with Lambert Eaton?
small cell/oats carcinoma of the lung
How is Type III HSR mediated?
- Preferential sites and their associated diseases
glomerulonephritis (kidney), arthritis (joints), vasculitis (small vessels)
What is an example of a local Type III HSR reaction?
- booster shot associated; reaction to horse Ab
What type of necrosis is associated with Type III HSR?
Fibrinoid necrosis (from neutrophils releasing enzymes) --> thrombi
In active SLE infection, where is complement taking place and what are the consequences in serum?
all complement occurring in wall of the blood vessels
- serum complement levels will be low
What is affected in vasculitis?
- predominant cell type?
The entire wall involved in necrosis
- dark cells would be neutrophils
What is an example of a local immune complex reaction?
- experimental vasculitis
Type IV HSR is __ mediated. and is considered a ___ type hypersensitivity.
- delayed type HSR (DTH)
Steps of a type IV HSR:
- example of type IV HSR
1. CD4 T cell recognition of antigen associated with MHC
2. Lymphokine production (IL-2, IFN-y)
3. recruit and activate macrophages
4. granuloma formation
When would a reaction occur in a type IV HSR?
- what type of test is an example of this
occurs within 1-3 days (24-72 hours)
- Tb test pt comes back wihtin 48 hours
Target cells of cytotoxicity in Type IV HSR
- example of this reaction
virus-infected cells, tumor cells, transplanted cells
contact dermatitis with Poison Ivy (severe form in pic)
What will react against graft antigens that will destroy tissue grafts?
The major antigenic difference between a donor and recipient that results in a rejection of transplants are differences in:
Direct graft recognition:
- cells involved
most attacks the graft parenchyma/tissue in general
- dendritic cell of graft to T cell of the host
Indirect graft rejection:
- cells involved
APC of host present to T cell
- get more humoral immunity which attacks blood vessels --> vasculitis
- attack of blood vessels = different prognosis and therapy
2 mechanisms of graft rejection:
1. T cell mediated cytotoxicity (direct)
- destruction of graft interstitial cells
2. Antibody mediated reaction (indirect)
- destruction of graft vasculature
Hyperacute transplant rejection
- occurs within minutes to hours
- due to pre-formed antibodies to transplant
Ig and complement deposited in vessel wall --> endothelial injury/thrombi (normally type III)
kidney cortex undergoes necrosis
What are the typical serum levels/urine characteristics in a patient with kidney failures?
rise in creatinine and BUN
- oliguria (decreased output of urine)
What type of infarct occurs in Type IV associated kidney failure?
Ab attack blood vessel --> damage endothelium --> thrombi --> white/pale infarct--> kidney will NOT survive
Acute transplant rejection (pathogenesis)
within days of transplantation/suddenly months or years later (after immunosuppression is tapered/terminated)
Clinical signs of acute transplant rejection:
sudden onset fever
acute renal failure
Which immune mechanisms predominate in acute transplant rejection?
cellular or humoral
If there is a a graft infarct, which transplant rejections could be presenting, and what distinguishes between them?
acute or hyperacute
time frame distinguishes (hyper = min-hrs; acute = days/mo/yrs)
Cellular immune mechanism (transplant rejection)
- how can you test to see if this is the mechanism occurring?
extensive interstitial inflammation (lymphocytes)
- can give high dose immunosuppressive therapy and they respond
Humoral Immune mechanism (transplant rejection)
- how can you test for this?
associated with deposition of the complement breakdown product C4d (preceded during activation of ADCC)
- results in infarct -- will not respond to high dose immunosuppressive therapy
What is the histological presentation of acute cellular rejection?
a lot of lymphocytes
- attack the parenchyma (like tubule)
What will the outside of the kidney appear as if there is acute rejection?
dark areas that may be areas of hemorrhage
What are the defining characteristics of chronic transplant rejection? How would the patient present?
- presents clinically with progressive renal failure manifested manifested by a rise in serum creatinine (over 4-6 months)
What is the morphology that occurs in chronic transplant rejection?
dominated by vascular changes
1. intimal thickening
2. glomerulopathy (duplication of BM)
3. peritubular capillaritis (mulitlayering of BM)
What is the histology presentation of a patient with chronic transplant rejection?
- lymphocytes involve the blood vessel
- slow narrowing of the lumen --> ischemia --> atrophy
endothelial cell hyperplasia
- tubules below the blood vessels are atrophic
dots are lymphocytes that release cytokines to stimulate cell proliferation (= multiple glomeruli)
What is the mechanism of cyclosporine?
blocks the activation of TF for cytokine genes (IL-2)
- block proliferation in BM; prevent host system from attacking the graft
Mechanism for Azthioprine as an immunosuppressive agent
inhibits leukocyte development from bone marrow precursors
mechanism for monoclonal anti-T cell Ab as immunosuppressive agent:
opsonize and eliminate T cells
Mechanism for mycophenolate mofetil as immunosuppressive agent
inhibits lymphocyte proliferation
Mechanism for Tacrolimus (FK506) as immunosuppressive agent
used a lot
- inhibits T cell function
Which opportunistic infection is a classic presentation in transplant patients on immunosuppressive therapy?
CMV is classic for transplants
What is the appearance of the kidney if a patient presents with chronic renal failure/ end-stage renal disease?
appear as if they have benign chronic HTN
atherosclerosis (AAA risk) seen in the aorta
Where is a transplanted kidney placed?
more anteriorly as a precaution, for better access
Graft vs. Host
- when it occurs
- classic patient
- classic transplant
when immunologically competent cells or their precursors are transplanted into immunologically crippled patients
- AID/SCID patients = classic
- site = hematopoietic stem cell transplantation
Injuries that occur in a graft vs. host rejection:
1. skin (rash) -- burn-like appearance
2. GI (diarrhea and abdominal pain)
3. liver (increased enzymes: ALT, AST) + jaundice
When will a bone marrow transplant rejection appear?
EX: tissue + mechanism of damage
very fast - within days
- begins to attack patient tissues -- liver biopsy = cholestasis = conjugated bilirubin building up from liver failure = jaundice
What is an example of a single organ disease?
What is an example of a multi-systemic disease?
Theories of autoimmunity
Theories of autoimmunity MOA and processes
- decreased suppressor T cell function
- increased helper T cell function
- release of sequestered antigen
polyclonal B cell activation
self-antigen modification by drugs/microorganisms
cross reaction (antigen with similar makeup to normal tissue)
Examples of autoimmune release of sequestered antigen:
What is the genetic factor HLA-DR3 associated with?
Type I DM
SLE, Sjorgen syndrome, graves, MG
What is the genetic factor HLA-DR4 associated with?
Type 1 DM, Rheumatoid arthritis
What is the genetic factor HLA-B27 associated with?
- bony fusion of the spine (young males); extraintestinal manifestation of IBD
Homogenous (diffuse) nuclear pattern
in certain disease, Ab against a portion of the nucleus so immunofluorescence shows which is involved to help diagnose
Rim (peripheral) pattern ANA
- disease association
sometimes in ds DNA
seen in homogenous; common for person with autoimmune disease to get another one
Speckled nuclear pattern
speckling of RNA and DNA
Nucleolar pattern on immunoflouresence
Antibodies to RNA
ANA- anti-nuclear antibody; sensitive but not specific so cannot be used to make a diagnosis
systemic lupus erythematosus (SLE)
- demographic commonly affected
- timeframe presentation
chronic; remitting and relapsing illness characterized by injury to skin, joints, kidneys, and serosal membrane
- common and severe in African American women
What is the etiology of SLE?
failure of regulatory mechanisms that sustain self-tolerance
- ANA sensitive but nonspecific for SLE
- Abs to dsDNA and Smith antigen = virtually diagnostic for SLE
- anti-phospholipid Abs
- Abs against RBC, WBC, platelets
What is the mechanism of anti-phospholipid antibodies?
bind to cardiolipin causing biological false positive test for syphillus (VDRL)
May alter in vitro clotting test of PTT (Lupus anti-coagulant)
Pathogenesis of SLE
- immunological factors
1. Genetic factors:
- increase risk in family members
2. environmental: certain drugs, sex hormones, UV light
3. immunological factors: helper T cell-dependent B-cell response, Type III HSR (fibrinoid necrosis)
What is the effect of SLE on the skin?
erythema of facial (butterfly) area exacerbated by sun -- aka maculopapular rash, facial, malar
liquefaction of epidermal basal layer with vasculitis
deposit of Ig and complement at derm-epidermal junction on IF
What will you see in immunofluorescent staining of skin in SLE patient?
liquefaction of epidermal basal layer with vasculitis
- above line is epidermis
- below line is dermis (BM / basal layer of the epidermis)
What is the result of SLE on the kidney?
1. minimal / no detecable Ab
2. mesangial lupus nephritis
3. diffuse proliferative glomerulonephritis
4. membranous glomerulonephritis
What is the diffuse proliferative glomerulonephritis?
most common and worst prognosis for SLE patients
- causes nephrotic syndrome = compression on capillaries = HTN and hematuria
Membranous Glomerulonephritis (Wire loop)
- HSR type
loops are open but the walls of the loops are thick due to complement and IG deposition
thickening of BM --> nephrotic syndrome
What is the classic appearance on immunofluorescence of the glomerulus undergoing glomerulonephritis?
- give an Ex of disease
- outline the capillaries
- Ig and complement are lit up
Ex: good pasture syndrome (Type IV)
Which is the only syndrome associated with glomerulonephritis that has linear immunofluorescence?
good pasture syndrome
- seen in young males
What is the effect of SLE on the cardiovascular system?
- what will be a clinical feature
primarily = pericarditis = usually fibrinous pericarditis
- "friction rub" on auscultation
- endocarditis (Libman-sacks) -- vegetations on both side of valve leaflet (anterior and posterior )
- Coronary artery disease
SLE effect on joints:
- joint pain but no joint deformity
(Rheumatoid arthritis also joint with no deformity )
SLE is an example of what type of hypersensitivity
Type 2 HSV presentations (hematological effects)
Other effects: Type III HSR
Clinical course of SLE (chronic history)
characterized by flare-ups and remissions
exacerbation associated with hypocomplementemia + treated with corticosteroids
What is the most common cause of death in SLE patient?
renal failure and recurrent infections (between flare ups)
Variant of Systemic erythematous
1. discoid lupus erythematous - negative dsDNA ab test, plaque-like skin lesion and visceral involvement
2. drug induced lupus: positive ANA, negative dsDNA
Drugs that are associated with drug-induced lupus:
Rx: stop giving the drug!!!
Sjorgen syndrome is the results of:
lymphocytic infiltration and fibrosis of the lacrimal and salivary glands
- unilateral or bilateral swelling by the mandible or angle of the jaw
Primary form of Sjogren's Syndrome presents with:
dry mouth (xerostomia) and dry eyes
Secondary form of Sjogren's syndrome is:
- seen in 75% of patients
serological markers that are seen in 90% of Sjogren's patients:
SS-A (Ro) and SS-B(La)
What is the typical demographic for Sjogren syndrome?
- 50s to 60s
(much older than Lupus)
What can result is the tears do not protect the cornea?
- gets scarred
Dryness of the mouth caused by reduction of saliva
____ gland is enlarged in half patients with Sjogren's syndrome
Do patient's with Sjogren have any other disease presentations?
most commonly another autoimmune disease (rheumatoid arthritis)
lacrimal and salivary gland inflammatory involvement
lacrimal and salivary gland enlargement (like is Sarcoidosis or lymphomas)
Biopsy of the lip is essential for diagnosis of which disease? why?
- looking for salivary gland involvement
There is an increased risk for development of ______ in Sjogren
marginal zone lymphoma (MALToma)
How can a MALToma be treated and which infection is it associated with?
- H. pylori
Histological biopsy of the parotid in Sjogren's
corners = normal tissue; middle = problem of lymphocytes attacks the large and small ducts
If there are atrophic ducts being attacked by lymphocytes in Sjogren's the CT present will eventually be:
What is scleroderma (systemic sclerosis)?
fibrosis in skin and multiple organs
What are the 2 major categories of scleroderma, and what syndrome is associated?
- CREST syndrome
What is a trigger for excessive fibrosis?
abnormal immune responses and vascular damage
Autoantibodies that are found in patient's with Scleroderma:
1. ANA (screen)
2. anti-Scl-70 (diffuse form)
3. anti-centrometric (CREST syndrome)
What is the morphology of the limited form of Scleroderma (CREST)
2. Raynaud phenomenon
3. Esophageal dysmotility (dysphagia)
5. Telangiectasia (dilation small vessels)
Morphology of the diffuse form of Scleroderma:
worse prognosis than CREST
1. thinning of epidermis
2. GE reflux
3. kidney - obliterate lume --> malignant HTN
4. Lung interstitial fibrosis
5. heart = pericarditis with effusion.myocardial fibrosis
What is the pathogenesis of the development of malignant HTN in patient's with diffuse Scleroderma?
obliterating the lumen in kidney --> decrease blood flow to the JG cells (tricking body that there is low blood volume/ hypotension) --> MALIGNANT HTN
because blocking the larger blood vessels (benign in Lupus)
A patient with scleroderma will complain of:
tightness in skin; lack of appendages (no hair follicles)
- autoamputation (falls off on its own)
Dermis with no appendages, will have thinned out bundles of __, which makes the histology similar to that of a ____.
Clinical features of diffuse Scleroderma:
- primarily seen in women; peak in 50-60 age group
- Raynaud phenomenon, dysphagia, respiratory difficulties, arrhythmias, cardiac failure
- ominous manifestation: malignant HTN with subsequent renal failure
What is the typical demographic for a primary immunodeficiency?
X-linked Bruton Agammaglobulinemia
- gene mutation
- age manifestation
- absence of:
BTK gene = no pre-B cell differentiation
males at ~6 mo. when maternal Ig depleted
recurrent pyogenic bacterial infection
Absent: - germinal centers
- plasma cells throughout the body
What type of infection can patient's with X-linked Bruton agammaglobulinemia handle?
viral fungal infections since they have intact T-cell immunity
Which bacterial infections are Agammaglobulinemia patients most frequently infected with?
Strep, Staph, Haemophilus
Common Variable Immunodeficiency (CVID)
hypogammaglobulinemia -- B cells fail to mature to plasma cells
- B cells become hyperplastic to try to make more plasma cells
increased incidence of autoimmune disorder
Isolated IgA deficiency:
most common of all primary immunodeficiency disorders
- European descent (Caucasian)
- failure of selective IgA B cells to become plasma cells
- recurrent sinopulmonary infections + diarrhea
most are asymptomatic
anaphylaxis to IgA-containing blood products (transfusion from rare donor pool)
DiGeorge Syndrome (Thymic Hypoplasia)
- undeveloped 3rd and 4th pharyngeal pouches (abnormal facies, thymic and parathyroid hypoplasia)
= selective deficiency of T cells
susceptible to viral fungal infections
defect in humoral immunity/T-cell immunity
- bacterial, viral, fungal infections
AR and X-linked
AR manifestations of SCID:
ADA deficiency --> accumulation of toxic products in B and T cells = defective lymphocyte function
X-linked manifestations of SCID:
associated with mutation
SCID is associated with a mutation that affects a protein shared by the receptors for :
IL-2, IL-4, and IL-7
What the main treatment for patient's with SCID:
- what is a possible complication
bone marrow transplant
- complication = graft vs. host disease
acquired immunodeficiency syndrome (AIDS)
caused by retrovirus (ssRNA; reverse transcriptase) of the lentivirus family
- caused by HIV 1 and 2
homosexual, IVDU, contaminated blood products, hemophiliacs, passage of virus from mom to baby (parturition, breast milk, transplacental)
With the HIV-1 infection being a possible cause of AIDS, the virus has to have___ entry
CD4 T cells have an affinity to which receptor in AIDS?
- infective receptor with high affinity
Which cells in HIV are responsible for latency period?
macrophages and follicular dendritic cells
Macrophages are used to transport the HIV virus to:
Screening test and confirmatory tests for AIDs:
screening is ELISA - test for Abs (3-7 weeks for enough ab to be produced)
confirm: Western Blot to look for the viral particles
With an inversion of CD4:CD8 ratio, how can the CD4 cells die:
- results in CD4 count going down
1. cytopathic effect of virus
3. killing by CTLs
Acute phase of viral-host interaction in HIV/AIDs:
- CD4 count
- viral replication levels
initial 6-12 weeks
high viral replication
- CD4 count going down
- asymptomatic/nonspecific symptoms
Chronic phase of HIV/AIDs
- CD4 count
- viral replication levels
Cd4 cells that are infected migrate to the lymph nodes
months = years
low level viral replication
Crisis stage of AIDs
- CD4 count
- viral replication levels
increased viral replication with decreased CD4 count (<200)
- long lasting fatigue, weight loss, diarrhea (STDs help the virus)
macrophages release the virus
What are differentials that can be associated with AIDs?
Patient with full blown AIDS is susceptible to:
- respiratory infection
- fungal infection from pigeon droppings
- cat feces
What is the oral lesions that are seen in a patient with AIDs
- What is a more severe form that can result in?
oral candidiasis (scrapes off )
Leukoplakia: white patches involving the oral mucosa --> squamous cell carcinoma of oral cavity
Candidasis can disseminated and cause:
- more severe
associated with AIDs in aggressive and metastasis
- associated with Herpes type 8
- homosexual =/bisexual males
Multiple KS lesions
involving the liver/stomach
- begins where
biopsy of Kaposi's lesion
sarcoma so it should be spindle shaped
extravasation of RBCs (not in true blood vessels
high grade B cell lymphoma
- seen in brain
- associated with EBV
Carcinoma of the cervix:
- viral association
- what is seen in homosexual/bisexual patients
see squamous cell carcinoma of anus associated with HPV
Neurologic disease/ Sx associated with AIDs:
CMV = blindness/retinitis
eosinophilic extracellular protein that builds up in organs = dysfunction
Congo red stain
- pink with this stain
If you put congo red stain under polarizing light, what is the appearance?
apple green birefringence
The best way to monitor patients with AIDs is using:
the viral load
- better indicator of the CD4 levels
Pathogenesis of amyloidosis
- what are the 2 major types:
- amyloid of light chains
2. AA- amyloid association
1. Plasma cell dyscrasia : causing deposition of protein derived from immunoglobulin light chains
2. Associated with multiple myeloma : Bence Jones proteins
chronic inflammatory condition like TB or rheumatoid arthritis
- liver will start kicking out amyloid as phase response for buildup
Kappa or lambda light chain derived
- associated with immune dyscrasia (primary)
non-immune globulin; associated with chronic infection (secondary type)
Localized dialysis-associated amyloidosis from beta-2-microglobulin (from MHC-1); usually presents as carpal tunnel syndrome (or other joints/tendon sheaths)
seen in Alzheimer disease
seen in older patients
- systemic senile amyloidosis and familial amyloid neuropathies
Calcitonin- associated with medullary carcinoma of the thyroid
Parafollicular C cells make up this tumor and secrete calcitonin - amyloid produced
islet amyloid peptide, associated with type II diabetes
plaque accumulation, can get so large the patient cannot breathe
Congo red stain in the liver of a patient with amyloidosis
amyloid deposits in blood vessels
- involves the space of disse (between hepatocytes and sinusoids)
ito cells (associated with vit A) found there
Amyloid under polarized light:
- since stained with congo red, the light will present the tissue as apple green with birefringence
Congo red biopsy of the kidney:
- deposits in the glomeruli involves the BM --> nephrotic syndrome
- albumin coming out = edema
compression of blood vessels
Apple green birefringence occurs:
under polarized light after tissue is stained with congo red
- glomerulus and other blood vessels
Clinical features of amyloid:
- GI tract
heart: restrictive cardiomyopathy
kidney: nephrotic syndrome
- over 50 y/o
If you suspect that the amyloid is systemic, what should you biopsy?
abdominal fat, anal area (easy access)
What is the vaso vasorum?
small vessel networks that supply the outer media of large arteries
What are characteristics of elastic arteries?
high elastin content of the media
- allows blood to be propelled throughout the body
- if less compliant = raises systolic blood pressure (expand in systole + recoil in diastole)
What are characteristics of a muscular artery?
responds to autonomic and metabolic factors --> vasoconstriction or vasodilation
= regulates regional blood flow and blood pressure
Small artery and arteriolar function
within tissues and organs
control blood flow to capillaries
Capillaries are ideal for:
What is the histological presentation of a small muscular artery?
reduced media thickness
- in tissue and organs
What the histological appearance of an arteriole?
1-2 layers of smooth muscle
- controls flow to capillaries
___ flowing through the capillary
Venous circulation carries ____ of the blood volume
veins with thinner, and less ridged walls =
compression, infiltration by inflammation and tumors
Reverse in blood flow is prevented by:
liver and renal endothelial cells are =
fenestrated for filtration
How do endothelial cells regulate resistance?
by regulating smooth muscle tone
What are some factors that can influence the endothelial cell regulation
During anaphylaxis, mast cells cause:
endothelial cytoplasm contraction
What can occur after endothelial cytoplasms contraction has taken place?
intravascular fluid moves to extravascular space = edema = reversible (no injury)
blood pressure (BP) measures:
systolic (max pressure) /diastolic (minimum)
During HTN, the arterioles are:
a point of principal resistance to blood flow
If you 1/2 the diameter, what is the effect on resistance?
increases resistance by 16-fold
Sustained diastolic pressures above ____mmHg or sustained systolic pressure above ____mmHg are associated with increased risk of atherosclerotic disease
89 mmHg; 139 mmHg
Threshold for patients at risk of cardiovascular disease?
there is no rigidly defined threshold
Increased pressure in a patient, will result in:
increased risk and detrimental effects
HTN can be asymptomatic and remain clinically silent for years, what are other symptoms that can be a sign?
headache, vision changes, chest pain, nosebleed
What are secondary effects that HTN can lead to?
LV hypertrophy, cardiac failure, cardiac failure, benign nephrosclerosis
Risk: ischemic heart disease, stroke
What percentage of HTN is idiopathic?
- what are other names for idiopathic HTN?
AKA essential/primary HTN (cause unknown)
Secondary HTN is related to which processes?
renal or adrenal disease, renal artery stenosis, or other identifiable causes, genetic
If Primary (Essential) Hypertension is untreated it can result in:
hypertensive retinopathy -- flame hemorrhages
cotton wool spots "copper wiring" -- "AV nicking" and papilla edema
Genetic factors that contribute to primary/essential HTN?
- demographic common
decreased sodium excretion = increasing systolic + diastolic BP
- more common in black Americans than white Americans
What are potential effects of HTN on the heart?
1. ventricular hypertrophy
2. reduced CO due to less BV in ventricle (end diastole) = increased atrium P and V
3. can lead to kidney damage
4. heart failure and myocardial infarctions
Which cells produce renin and where?
- around glomerular afferent arterioles
Renin is released in response to:
1. low BP
2. low Na+ levels
* increased Na+ resorption
Which enzyme leaves plasma angiotensinogen to angiotensin I?
Angiontensin II function:
2. stimulate aldosterone secretion
3. tubular sodium resorption
goal: retain fluid
function of aldosterone is to
inhibit sodium resorption = excretion = diuresis
- systemic vasodilation = lower BP
Function of aldosterone is to
increase sodium absorption (and water with it)
adenoma in adrenal cortex
Sx: hypernatremia, hypokalemia, increased BP
shuts off RAAS = low plasma renin
- effects on urine
- serum levels
hyponatremia --> hyperkalemia
increased urine sodium and decreased urine potassium
water follows salt = hypotension
What is malignant HTN?
- BP value indicating this
- common predisposition
- kidney appearance
rapidly rising pressure, usually young African American males
- usually in patients with pre-existing HTN
death within 1-2 yrs = CHF, renal failure, CVA
What are the 2 types of atherosclerosis?
hyaline thickening in arteriolar walls from increased protein deposition
(hyaline deposition in arteriole wall)
What are causes of hyaline atherosclerosis?
1. long standing HTN
- results in
- caused by
caused by malignant HTN
- malignant nephrosclerosis "flea bitten kidney"
An acute increase in BP in a patient with malignant HTN is caused by:
basement membrane duplication/smooth muscle hyperplasia
What are the 2 types of histological presentation of hyperplastic atherosclerosis?
1. fibrinoid necrosis (fibrin deposits in vessel wall)
2. hyperplastic arterioles "onion skin" appearance of arterioles
Hyperplastic atherosclerosis can also be described as
What are some causes of secondary HTN?
1. adrenal- hyperaldosteronism (Conn)
2. Renal- atherosclerosis/stenosis
** 3. renal artery stenosis
4. aortic coarctation
Effects of secondary HTN caused by renal- atherosclerosis/stenosis:
reduced BF = increased renin
- increased BP
The most common cause of secondary HTN:
Renal artery stenosis
What is the effect of aortic coarctation on BP?
decreased BF to the kidneys = increased Renin = decreased aortic elasticity
increased BP above coarctation
A common cause of HTN in young women is:
- oral contraceptive increase angiotensin
Types of arteriosclerosis
1. Monckeberg medial sclerosis
Monckeberg medial sclerosis
usually found in radial/ulnar artery
- calcification of muscular arteries (not cause of stenosis)
- no clinical significance, older patients
- dark purple = calcification
small artery/arteriole disease
thickening and narrowing of lumen - ischemia with HTN
intimal fibrofatty plaque = atheroma
ischemic heart disease (IHD) with MI, strokes, gangrene of extremities
50% of deaths in western world
Framingham Heart Study (1948)
Longitudinal cohort study designed to identify risk factors associated with cardiovascular disease
-Term "risk factor" was popularized after repeated use in this study
Risk factors for ischemic heart disease (IHD)
- why they are risk factors
before menopause-estrogen protective
after menopause - loss of protective estrogen = major risk increase = atherosclerosis related disease increase = catch up to men
3. genetics - most important risk factor
- family history of hypercholesterolemia, HTN, diabetes
LDL vs. HDL
LDL = bad cholesterol; transports cholesterol to tissues
HDL = good cholesterol; mobilizes cholesterol from plaques
If there is increased serum cholesterol or LDL, what is the risk of atherosclerosis?
increased risk of atherosclerosis
If there is an increased HDL, what is the associated risk with atherosclerosis?
decreased risk of atherosclerosis
Modifiable risk factors for ischemic heart disease:
5. lack of physical activity
6. stressful life (type A)
7. use of oral contraceptives
C-reactive protein (CRP)
- what does it assess
- marker for:
good test to perform for risk assessment
- circulating marker of inflammation
20% of all heart disease events occur in the absence of
known risk factors
What does the vascular response to injury cause?
thickening of the intima = stenosis and vascular obstruction
How does thickening of the intima occur in vascular injury?
1. smooth muscle proliferation
2. matrix deposition
3. intima thickening
What is the earliest event/trigger for atherosclerosis?
Earliest pathological change of atherosclerosis?
dysfunction from endothelial injury
(not seen but present)
intimal thickening- earliest thing that can can be seen with a microscope
Pathogenesis of atherosclerosis is characterized by:
intimal plaque thickening (atheroma) and weakening of underlying media
Endothelial injury leads to what in the vessel wall?
leukocyte adhesion and vascular permeability
What is the role of cytokines during endothelial injury?
call the smooth muscle cells to the intima
Which cells engulf lipid (oxidized LDL) during atherosclerotic formation?
macrophages and smooth muscle
Oxidation of LDL by which cells can cause the formation of foam cells?
macrophages and smooth muscle cells
LDL is needed to create the foam cells
Collagen and ECM is deposited in the wall by:
- which one only creates ECM?
smooth muscle cells
- only smooth muscles create ECM
Major components of an atherosclerotic plaque
1. fibrous cap
2. necrotic center (constantly changing, not always present)
2 stages of an atherosclerotic plaque
1. Fatty streak (reversible) = earliest intimal thickening
- intimal aggregation of foam cells (macrophage only at this point)
2. Atheromatous plaques = intimal thickening and lipid accumulation
3 parts of atheromatous plaques:
1. Cells - smooth muscle, macrophages, T cells
2. ECM - collagen, elastic fibers and proteoglycans
3. Lipids -
Are fatty streaks reversible or irreversible?
- first noticeable sign of damage of foamy macrophages
Mild atherosclerosis features:
smooth muscle hyperplasia, some lipid deposition in atheroma/plaque
- commonly in aorta
Clot disruption in atherosclerosis can cause
plaque formations are normally seen in patients who are in 70s-80s who may not have other risk factors
Most common location of atherosclerosis:
Complications that can occur from atherosclerosis:
1. vessel occlusion/thrombosis
2. HTN from renal artery stenosis (RAAS- secondary HTN)
3. peripheral vascular disease (PVD)
What are symptoms associated with peripheral vascular disease?
Claudication = pain, weakness, numbness, cramping with activity (indication of atherosclerosis)
- Acute peripheral artery occlusion sx (5P's)
pain, pallor, paraesthesia, paralysis, pulseless
ischemic necrosis - gangrene
cerebral atrophy (circle of willis)
atheroembolism (release debris into blood stream)
What is the most common atherosclerosis clinical disease?
abdominal aorta - large elastic arteries are most affected
When is atherosclerosis classified as critical stenosis?
70% decrease of lumen cross-sectional area
- chest pain with exertion = stable angina
What are the 2 types of plaques:
1. stable plaque:
- increased smooth muscle cells = extracellular matrix
2. unstable plaque:
- increased inflammatory cells = breakdown matrix
Components of an atherosclerotic stable plaque:
- clinical presentation of patient
necrotic core with cholesterol clefts
Not acute changes, but pain with exertion/increased demands
not meeting increased O2 demand (with exertion)
Acute change of unstable plaque:
1. plaque erosion/rupture = partial/complete vascular thrombosis
- MI/Cerebral infarct
2. acute plaque change = sudden onset
- hemorrhage into atheroma
Histological features of an unstable/complicated plaque
thin caps, large lipid cores, dense inflammation
sudden and fatal outcomes:
- acute plaque rupture
MI and death
What are aneurysms?
- most important causes?
localized abnormal dilation of the blood vessel/heart
What are the morphological types of aneurysms?
- ovoid configuration/circumferential dilation
- bubble-out pouching "berry aneurysm"
- column of blood separating media (aortic dissection, tunnels between layers of wall)
vessel wall intact or thinned ventricle wall of heart
defect in the wall causing blood to collect outside the vessel
- bound by extravascular tissue
Atherosclerotic aneurysm location
predominantly abdominal aorta
Syphilitic aneurysm location
ascending and arch of aorta (tertiary syphilis)
Berry aneurysm location
- disease association?
cerebral arteries at circle of willis
- associated with polycystic kidney disease
damage of the wall of any blood vessel by infectious agents
Hypertensive aneurysm location
ascending or thoracic aorta
Abdominal aortic aneurysm is due to:
- usually located at
- clinical presentation
- medial destruction of vessel
located usually below renal arteries and above the bifurcation of iliac
over 50, usually males, more commonly smokers
Clinical: abdominal bruits/pulsatile mass
- new onset of cold, pale lower limb = atheroembolism of AAA
How are AAA discovered?
clinical presentation suggestive?
pulsating abdominal mass/bruit
can present as low back pain/abdominal pain
- embolism form atheroma/mural thrombus to extremities or kidney
In a AAA what is the rupture triad?
sudden severe left flank pain, hypotension, pulsatile mass
Thoracic aortic aneurysm
- disease associated
usually due to HTN
Marfan's syndrome - idiopathic cystic medial necrosis
- respiratory difficulties
- difficulty swallowing
- cough due to compression of laryngeal nerve
Syphilitic aneurysm/aortitis is a complication from:
tertiary syphilis (Treponema pallidium)
What does treponema pallidium infect?
vaso vasorum of the ascending and transverse aorta
Vasculitis is called ____ which will lead to ___
endarteritis obliterans ; medial necrosis
Weakness and dilation of the aorta wall and valve ring will lead to which cardiac features?
left ventricular overload and hypertrophy
What is it called when there is irregular intimal wrinkling and scarring from inflammation?
tree bark / syphilitic aortitis
- what it is
- most common
saccular dilation usually around circle of willis and base of brain
- junction of communicating branes with the anterior cerebral artery (ACA)
Why is there a risk with junction of communicating with main cerebrals?
no internal elastic lamina/smooth muscle of the split/junction '
has area of natural weakness = vulnerable to increased tension
What is the classic onset of a berry aneurysm?
- which disease process is it normally associated with?
"worst headache i have ever had"
- associated with polycystic kidney disease
What is a dissecting aneurysm of the aorta? (dissecting hematoma/aortic dissection)
false aneurysm with intimal tear allowing blood to enter media
An intimal tear is secondary to:
1. HTN - increased pressure + poor vascular perfusion= medial degeneration
2. Marfan Syndrome
- idiopathic medial necrosis = weakness from Marfan's pathology
Mechanism of a dissecting aneurysm of aorta:
1. cystic medial degeneration (HTN, Marfan's, pregnancy)
medial ischemia = increased ground substance = medial "degeneration"
Major risk factor of dissecting aortic aneurysm:
- atherosclerosis is risk factor
Marfan syndrome, Ehlers Danlos
Clinical Sx of dissecting aortic aneurysm:
severe "ripping" pain in anterior chest radiating to back
new onset of diastolic murmur of aortic insufficiency = dissection near heart/aortic valve
widened mediastinum on CXR
hypotension bad sign
Where are most aortic dissections talking place
- common cause of death
most proximal ascending (worst) with/without descending aorta involvement (type A)
Type B = distal to subclavian
common cause of death = pericardial tamponade-- rupture through adventitia into surrounding cavity
What can an aortic dissection also cause?
- new diastolic murmur
- ischemia of bowel, limbs
Type B aortic dissection
distal to subclavian
What is getting damaged in the aorta during a type A aortic dissection?
dissection and hemorrhage in false lumen
cusps of aortic valve rupture
What is seen on the histology of an aortic dissection?
- false lumen created between media layers
- true aortic lumen
Prognosis of an aortic dissection
50% die within 48 hours
-2 week undiagnosed dissection = 75% mortality rate
inflammation of the vessel wall
1. immune mediated
3. physical and chemical injury
Clinical manifestations of vasculitis:
fever, myalgia, arthralgia, malaise
rash, petechiae, purpura
Immune mediated vasculitis mechanisms:
1. immune complex deposition (lupus, Hep B, Hep C)
2. Anti-endothelial cell Abs
3. Anti-neutrophil cytoplasmic antibodies
Immune complex deposition
- disorders associated
- SLE, Henoch-Schoenlein purpura, cryoglobulins
drug hypersensitivities and infections
Anti-endothelial cell antibodies:
- diseases associated
Type II HSR
1. Kawasaki disease - Ab to vascular endothelial cells
2. Good-pasture = Ab to BM
Anti-neutrophil cytoplasmic antibodies:
- what Abs react to
- cells involved
pts with vasculitis have circulating Ans that react with neutrophil cytoplasmic Ags
activate neutrophils = inflammation = endothelial cell damage
PRS-ANCA previously c-ANCA
Wegener's granulomatous = granulomatous with polyangitis
- microscopic polyangitis
- Churg-Strauss syndrome
Is polyateritis nodosa ANCA (+) ?
Which vessels does polyarteritis affect?
small and medium
- classified under medium vessel disease
Which diseases are classified under large vessel disease?
- histo appearance
1. Temporal Arteritis
2. Takayasu Arteritis
*Granulomatous on histo
- risk if untreated
most common form of vasculitis in elderly of U.S/Europe
- Segmental larger artery vasculitis, involving temporal and other cranial arteries = arteries of the head
Untreated = can lead to blindness - emergency!
Clinical presentation of temporal arteritis/giant cell arteritis:
throbbing headache (no response to NSAIDs)
tender temporal area, firm, nodular temporal artery
- visual disturbances (double vision)
- Jaw claudication
- polymyalgia rheumatica (proximal joint pain, morning stiffness)
Histology of temporal arteritis/giant cell arteritis:
segmental granulomas with giant cells and intimal fibrosis of vessel wall
- multi nucleated giant cells, histiocytes, lymphocytes
- negative results DOES NOT exclude diagnosis
- vessel involvement
demo: Asian women (japan) under 40 y/o
involve: large vessel; aortic arch and its major arches
diminished radial pulse -- subclavian artery affected (cold arms, discrepant BP between arms)
Histology of Takayasu arteritis
- extensive intimal fibrosis
Polyarteritis Nodosa (PAN)
- diseases associated
medium to small sized arteries
exception = does not involve lungs
Renal disease- HTN = causes more deaths
Tender subcutaneous nodules and "palpable purpura"
most common = abdominal pain and mononeuritis multiplex
Polyarteritis nodosa (PAN)
- risks if untreated
- 30% of cases associated with:
untreated = fatal = die from renal failure
common in young males
Hepatitis B surface antigen
What is the association of Hep B with PAN?
causes immune complex deposition
- can be P-ANCA positive = red herring -
drug abusers increased incidence (Hep B and C)
Polyarteritis Nodosa (PAN)
segmental, transmural. (full wall thickness) inflammation
fibrinoid necrosis and neutrophilic infiltrate
variable morphology/stage in the same blood vessel*** PAN FEATURE
most common cause of acquired heart disease in children
COVID 19 causes similar vasculitis in children
"mucocutaneous lymph node syndrome"
Clinical manifestations of Kawasaki disease:
high fever for more than 5 days
red/patchy red palms and sole = peeling, genital area
*** Significant because of coronary vessel involvement = aneurysm
Pathogenesis of Kawasaki disease:
coronary arteries are frequently involved with aneurysm formation
- vessels involved
- early vs advanced stage
demo: middle aged heavy smokers
vessels: artery, vein, perineural sheath
- tibial and radial arteries
early: intermittent claudication
Histo: abscess formation in vessel
Rx: cessation of smoking
If patient has a history of intermittent claudication:
- what other associated clinical manifestations
Thromboangitis obliterans. (Buergers)
+ loss of tips of fingers or toes with bone sticking out - gangrene
- which ANCA
multiple sites, non-specific
palpable purpura on skin
lesions are the same age
***Associated with p-ANCA (MPO-ANCA)
Clinical pf microscopic polyangitis/polyarteritis:
hemoptysis = cough = can be life threatening
proteinuria - kidney inflammation = rapidly progressive glomerulonephritis
Recent new drug prescribed:
Histology of polyangitis/polyarteritis
fibrinoid necrosis of vessel wall
nuclear dust and debris (necrotizing)
- classic sites affected
- ANCA associated
3. Kidneys - renal failure
- high sensitivity/specificity; NOT definitive
Clinical presentations of Wegener Granulomatosis:
- damage from chronic?
- URT Sx is what sets it apart from other vasculitides
chronic inflammation can cause destruction of cartilage, lung hemorrhage
Histology triad in Wegener's Granulomatous
1. necrotizing vasculitis
2. necrotizing granulomas in surrounding tissue (not vessel wall)
3. large areas of necrosis (geographic necrosis)
95% have PR3- ANCA (c-ANCA)
- triad of presentation
- if cardiac involed?
eosinophilic granulomatous with polyangitis
small vessel necrotizing vasculitis
- asthma: lung infiltrates
- allergic rhinitis
- peripheral hypereosinophilia
heart (cardiomyopathy) in 60% and accounts for 1/2 of deaths from disease
MPO-ANCA in 1/2 of cases (p-ANCA)
- histo features
- Churg-Strauss Syndrome
idiopathic disease of children often preceded by URT infection
- purpura -- legs, buttocks, knees
- abdominal pain
immune complexes with IgA deposits in wall of affected blood vessels
- clinical presentation
- HLA involved
1. oral ulcers
2. genital ulcers
associated with HLA-B51
- mediated by:
- what is it
immune complex mediated
acute inflammation of small vessels (purpura, glomeruli and GI may be involved)
Histo: leukocytoclastic vasculitis
A drug vasculitis is considered:
a hypersensitivity vasculitis
Connective tissue disease vasculitis such as ____ are considered ____ vasculitis
Microscopic polyangitis is a separate category of which ANCA?
MPO-ANCA (p-ANCA related)
Causes of microscopic polyangitis:
3. collagen vascular disease (lupus)
5. 50% are idiopathic
exaggerated vasoconstriction of arteries and arterioles
pallor and cyanosis
red, white, and blue color changes from proximal to distal
usually young women
can lead to atrophy -- ulceration and ischemic gangrene are RARE
Secondary Raynaud's phenomenon
- caused by
vascular insufficiency caused by other diseases
(lupus, scleroderma, Buerger disease)
abnormally dilated, tortuous veins
loss of vein wall support and valves incompetent with standing
- stasis, congestion, edema, pain, and thrombosis
creates chronic congestion = causes tissue ischemia
Varicose veins can secondarily cause __ dermatitis.
- primary disease
varices that shunt the blood through veins at gastroesophageal junction
risk: can cause fatal hemorrhage -- need to consider in alcoholic = vomiting blood
Periumbilical shunting causes:
pregnancy, straining to defecate
can bleed (bright red blood), thrombose and ulcerate
inflammation of a vein
A blood clot forming in the inflamed superficial vein
common in ppt with varicose veins, pregnant, immobilization, IV and IV drug use
Deep vein thrombosis
deep leg veins: site of >90% of cases of DVT
1. prolonged immobilization
2.adenocarcinomas (via hypercoagulability)
- Trousseau sign = changes location
- most commonly pancreatic adenocarcinoma
NO reliable signs/symptoms
- may have Homan sign/pain squeezing in calf
~15% of sudden deaths
Superior vena cava syndrome
dilation of veins of head, neck, and arms with cyanosis
Inferior vena cava syndrome
renal and hepatic carcinomas like to invade IVC
- lower extremity edema, distended and superficial abdominal veins and proteinuria if renal involved
- what it is
- common causative agents
acute inflammation elicited when bacterial infection spread into lymphatics
common agents: group A B-hemolytic streptococci
- red, painful subcutaneous streaks (inflamed lymphatics)
- painful enlargement of draining lymph nodes (acute lymphadenitis)
- sepsis (vessels)
- cellulitis, abscess (tissues)
- secondary + causes/results
- persistant edema = ?
primary = genetic
secondary = obstructive
- surgical procedures that remove groups of lymph nodes
- fluid accumulation + edema
persistant edema = peau d'orange (inflammatory breast cancer)
Lymphedema from filariasis aka
- where is fluid accumulating?
unilateral leg edema
Port-Wine Stain (Nevus Flammeus)
- results in
enlarge and thicken - do not regress
results: trigeminal nerve distribution = sturge-weber syndrome
- vascular abnormalities, seizures, mental retardation, hemiplegia
associated with pregnancy and liver cirrhosis = blanch when pressed
hereditary hemorrhagic telangiectasia
malformation of dilated capillaries and veins at birth
distribution: skin, mucosa, respiratory, GI tract
CAUSES EPISTAXIS (nose-bleeds)
- rapidly growing
- can be from trauma
in skin, subcutaneous tissues, mucus membranes
Infantile hemangioma of children
- classified into:
superficial = juvenile/strawberry hemangioma (damage if removed)
deep = large vascular spaces, can be in deep organ - cavernous hemangioma
grow rapidly for 18 months, regress by age 5-9
Congenital Hemangioma (CH)
rapidly involuting congenital hemangioma (RICH)
Non-involuting congenital hemangioma (NICH)
Hemangiomas can be associated with _________ disease:
Von Hipple Lindau disease
opportunistic infection of immunocompromised persons caused by Bartonella genus (gram negative)
Bartonella henselae - cats "cat-scratch disease"
Bartonella quintana - live, caused french fever in WWI
How can you tell if an angioma is lymphatic?
1-2 cm head and neck
- what syndrome is associated
- neck/axila of children = can get large and cause deformity
Glomus tumors - "Glomangioma"
- what it is
- cells involved
painful tumors arising from proliferation of glomus body smooth muscle cells
glomus cells - control thermoregulation
- found on distal digits - especially under fingernails
Kaposi sarcoma viral cause:
human herpes 8
Epidemic Kaposi's sarcoma
associated with AIDS
- most common HIV malignancy 2-3% of HIV patients in US
Endemic Kaposi's Sarcoma
seen in africa
Epidemic + endemic Kaposi's makes KS most common tumor in ___
Classic Kaposi Sarcoma
indolent course/not aggressive - remain local to skin
older European men, Ashkenazi Jews, Mediterranean
NOT HIV related
transplant-associated kaposi sarcoma
solid organ transplants
patches --> plaques --> nodules
Histology of Kaposi's sarcoma
- slit like spaces lined by variable atypical spindle cells with extravasation of RBCs
highly malignant tumor from vascular endothelial cells
often on scalp of old men
- lymphedema --> breast cancer
- radiation --> breast cancer
- chemical exposure - liver -> VAT
5 year survival ~30% BAD ACTOR
Clinical presentation of angiosarcoma
blend into tissue = hard to define/remove
Histology of angiosarcoma:
malignant spindle cells lining true vascular spaces
- very invasive into surrounding tissue
- stain used
VAT of chemicals
- Vinyl chloride
CD31 stain may be used to identify vessels
Cardiac output is defined as the amount of venous return to ___, since it is a ____ system.
right heart; closed system
How does blood flow through the body in terms of a gradient?
move down the pressure gradient
Which vessel is the area of greatest resistance? Why?
- protects capillaries and control regional blood flow
Since the arterioles have greatest resistance, what is required to maintain flow?
A drop in pressure
Since capillaries have a much larger surface area, what is the affect on blood flow?
Slows down flow for gas exchange
Large changes in pressure, proportionally cause an increase in...
(2x ∆pressure = 2x flow)
Veins contain valves, which ensure:
blood return (if complaint and low resistance)
Controlling diameter of a vessel has a profound effect on what?
- Hypovolemic shock + Anaphylactic shock (vasodilation)
If the following changes are made to the vessel, what is the result?
2x radius = __ flow
2x radius = ___ resistance
1. 16x flow
2. 1/16 resistance
Veins are most compliant, and they hold how much of the blood supply?
What about if the veins are dilated?
hold 2/3 blood supply
if dilated, amount increases septic shock/anaphylactic shock
What disease process occurs in older patient as their arterial compliance decreases further and increased pressure?
Formula for BP:
BP = CO x PR
Humoral factors that influence peripheral resistance:
1. constrictor examples
2. dilator examples
- Angio II
Neural factors that influence peripheral resistance:
Norepinephrine- Epinephrine- Angiotensin II - Aldosterone-
ADH/ Vasopressin -Thromboxane-
Nitric oxide -Histamine-
Carbon Dioxide -Acetylcholine-
Atrial Natriuretic Peptide -
(+ water and salt excretion)
If there is increased preload, what happens to contractility?
volume of ventricle before contraction (stretch)
EX of diseases with increased afterload?
pressure/force the heart must work against to eject blood from the ventricle
HTN and aortic stenosis = increased afterload
What factor can alter the contractility?
intrinsic strength/energy of cardiac muscle independent of preload
preload can alter contractility
If there is an increased venous return or increased ventricular EDV, what is the affect on stroke volume or cardiac output?
increased SV or CO
What is one way to increase preload that will not result in an increased cardiac output?
increased aortic pressure (increased afterload)
What are ways to increase preload?
1. increased atrial contractility
2. increased ventricular compliance
3. decreased HR
4. decreased venous compliance (vasoconstrict)
5. increased thoracic venous blood volume (respiration)
6. increased aortic pressure
Increased afterload = ___ cardiac work = ___ cardiac output
increased cardiac work; decreased cardiac output
Decreased afterload, will have what affect on the cardiac output, and why?
increased cardiac output
- less work required from the heart to eject blood
Decreased afterload = ___ cardiac work = ___ cardiac output
Decreased cardiac work; increased cardiac output
Boyle's law states that
the volume of a gas is inversely proportional to its pressure
(increased P = decreased V)
With an increased volume of the lungs, where does the air flow?
Flows in to the lower pressure lungs
is relaxation an active or passive process?
How is it possible for air to move from higher to lower pressure?
pleural surface seal created from the fluid in the pleural space
Inspiration __ the right atrium and right ventricle = what affect on the pressure?
expands RA and RV; dropping pressure
A drop in pressure during inspiration, pulls blood from ____ system into___.
venous system into the right heart
During isovolumetric relaxation, does the pulmonary valve or aortic valve close first?
aortic then pulmonary valve
- inspiration causing split of S2 (A2,P2) delaying closure of Pulmonic valve
During expiration, in which direction does everything get pulled?
towards the lungs
1. increased pulmonary flow/volume
2. transient decreased flow of blood from the lungs to LA
3. pull towards the lungs
What is happening in the left ventricle during inspiration?
lungs __ = ___ flow from lungs to LA = ___ left ventricular filling
deflate; increased flow; increased LV filling
What is the net effect of increase rate and depth of inspiration?
Increased left ventricular SV and CO
Respiration-Inhalation ___ blood flow to RA, due to...
what is happening to the left side of the heart in this case?
due to pull of negative pressure in the lungs
- decreased return to the left side of the heart for the same reason
Inspiration pulls blood towards the __
Why are right sided murmurs be increased with inspiration?
Why are left sided murmurs increased with expiration?
ex of auscultated murmur during exhalation
More volume into the left side
ex: aortic regurgitation (hold it)
Does vasoconstriction/vasodilation of the arterioles of the arterioles influence the venous return?
What will vasoconstriction of the arteriolar system due to venous return? Why?
decreases it; due to increased afterload and reduced cardiac output
Reduced output = ______
What is the effect of reduced afterload on CO and venous return?
increased cardiac output; increased venous return (VR)
Formula for cardiac output:
CO = HR x SV
How can we compensated for reduced output?
1. increased HR (CO=HRxSV)
2. Increased contractility of heart muscle
3. Increased preload (volume before contraction)
Blood pools in the lower extremities due to what?
What is used to prevent this?
It is due to pull of gravity and high vein compliance
- muscular activity prevents the pooling
If fluid moves from the interstitium due to increased pressure, what presents if it is deposited faster than lymphatics drain it?
Decreased venous return has what effect on SV and CO?
What can the patient present with?
decreased SV and CO
fainting due to low output if no compensation happened when standing up
What are the steps of standing compensatory mechanisms?
1. carotid baroreceptors = sympathetic outflow
- TPR/SVR - increased preload
- venous return
During exercise, what happens to the SV?
SV is increased at any level of exercise
- max HR does not change with conditioning
Coronary blood flow occurs during which phase of the cardiac cycle?
diastole for both rest and exercise
heart muscle during contraction constricts the vessels between muscle (coronaries lay atop of the muscle)
Pulmonary vascular resistance and SVR/TPR during exercise have what kind of compensation?
they both decrease
SVR/TPR = large decrease, dilation of skeletal muscle vascular beds
- venous system does constrict to have an increased venous return
Mechanisms leading to cardiac dysfunction:
1. failure of the pump
2. Obstruction of flow
3. Regurgitant flow
4. Disorder of cardiac conduction (arrhythmia)
5. shunted flow (ASD, VSD..)
6. disruption of continuity of circulatory system (rupture)
Heart failure occurs when
There is an inability of cardiac output to meet the metabolic requirements of tissues or organs
Common end stage of chronic heart disease:
chronic work overload (HTN, valve disease)
ischemic heart disease (post-MI)
What is meant by systolic dysfunction?
insufficient ejection fraction
decreased forward flow
- MI, dilated cardiomyopathy, valve disease
What is meant by diastolic dysfunction?
stiff ventricle, cannot relax during diastole
myocardial hypertrophy (HTN, DM, obesity, bilateral renal artery stenosis)
restrictive cardiomyopathy (fibrosis/deposition)
Diastolic dysfunction leads to :
- common in women over 65
When does high output cardiac failure occur?
- 2 most common examples
occurs when normal cardiac output cannot meet increased oxygen demands
1. increased metabolism - hyperthyroidism
2. decreased systemic vascular resistance direct increased flow into venous circulation
Ex: thiamine deficiency
Frequent causes of high output cardiac failure:
1. wet beri beri = thiamine deficiency
(circulatory = wet; neural = dry)
2. Graves disease (high metabolic rate)- Hyperthyroidism
3. Pregnancy (twin, triplet, etc)
4. Severe anemia
Causes of left sided heart failure (low output)
ischemic heart disease (IHD)
Aortic and mitral valve disease
Causes of right sided heart failure (low output)
Left sided heart failure
- what it is
- 2 causes
sustained increase in mechanical work from pressure, volume overload or trophic (hormonal)
1. Pressure overload (HTN) - sarcomeres in parallel = concentric increased in wall thickness
2. Volume overload - sarcomeres increased in series = dilation of wall
increase in ventricle wall thickness
increase in ventricle chamber size (dilated ventricle)
What is the best measure of hypertrophy in dilated heart?
weight, 2-4x normal
What happens to the vasculature of a hypertrophied heart?
there is NO increase in capillary number
- increased demands are NOT met with increased vasculature to supply the thicker muscle
Hypertrophy from regular strenuous exercise would be classified as what type of hypertrophy?
Hypertensive heart disease
- left sided vs right sided
left sided = systemic HHD
right sided = Cor pulmonale (from pulmonary hypertension)
Systemic hypertensive heart disease needs:
1. left ventricular hypertrophy (concentric)
2. Hx of pathologic evidence of HTN in other organs (kidney)
Clinical presentation of a patient with systemic hypertensive heart disease:
- may be asymptomatic with only EKG changes of LVH
- new onset a-fib from left atrial enlargement
Outcomes resulting from systemic hypertensive heart disease:
HTN-> atherosclerosis and increased hear muscle o2 demand
- Ischemic heart disease
Normal vs hypertrophic myocardium
- enlarged myocytes
- enlarged "boxcar" nuclei
What does "right dominant heart" mean?
Right coronary supplying 1/3 of the interventricular septum
is the delay of the AV node
- allows for filling of the ventricles
Clinical features of Left heat failure:
- frothy sputum
- basal rales
Left sided heart failure is related to:
- passive congestion of lung
- stasis/reduced flow through left
-inadequate tissue perfusion
Left sided heart failure can have what kind of effects in the heart, lung, and brain?
- LV hypertrophy/dilation
- LA dilation and valve dysfunction
Hypertrophy impairs __ filling, leading to ___ with increased risk of _______
leading to atrial enlargement with an increased risk of atrial fibrillation
Which vessel perfuses the anterior wall of the left ventricle?
Left anterior descending (LAD)
40-50% of infarcts
Clinical features of right sided heart failure:
all related to increased congestion of venous circulation
- dependent edema
- jugular vein distension
enlarged tender liver = nutmeg liver
- could get enlarged spleen/kidney
Right sided heart failure can cause what presentations in the heart, brain, and passive congestion in which organs?
- RV hypertrophy/dilation
- RA dilation
- hypoxia (poor volume output)
right ventricular hypertrophy and heart failure due to primary pulmonary hypertension
NOT left sided heart disease
Acute cor pulmonale
Dilation of right heart from pulmonary thromboembolism that can lead to sudden death
chronic cor pulmonale
right ventricular hypertrophy secondary to prolonged pressure overload seen in association with pulmonary hypertension disorders
RV hypertrophy and Cor pulmonale can occur from which disease?
- what is the effect on alveolar capillaries?
Can occur from Emphysema/COPD/Smoking
alveolar capillary stretching/flattening = increased pulmonary pressure
Cor pulmonale is a ___ sided heart failure caused by a primary __ problem.
right sided; primary lung problem
NOT caused by LHF
What is the dominant cause of ischemic heart disease?
insufficient coronary perfusion relative to myocardial demand
What is present in 90% of the cases in patients who have Ischemic heart disease/CAD?
Clinical syndromes of patients with Ischemic heart disease/ CAD?
- which are referred to as acute coronary syndrome?
1. angina pectoris "chest pain"
2. MI - frank myocyte necrosis
3. sudden cardiac death
4. Chronic IHD
angina pectoris (chest pain)
not severe enough of an occlusion to cause infarct
2. unstable (crescendo, pre-infarct)
3. Printzmetal (transient ST elevation)
Which subsets of angina pectoris may have ST depression?
stable and unstable
When is death estimated to occur in sudden cardiac death (SCD)?
within 1 hour of symptom onset
- duration + Sx
15 sec- 15 minutes
- deep poorly localized pressure, squeezing, burning with radiation to left arm or jaw
- fixed atheromatous narrowing - generally not acute plaque disruption
- exacerbation: physical activity, emotional excitement, stress
- alleviation: vasodilators
- may have ST segment depression with exercise or may be normal
Printzmetal (variant) angina
younger women, smokers, cocaine, alcohol
- coronary artery spasm- unrelated to activity (usually sleeping)
- pain at rest, lightheaded, excessive sweating and cannot be induced with stress test (exercise tolerant)
transient ST segment elevation- mimics acute MI
- No Q wave or T wave inversion (as in MI)
Unstable (preinfarction, crescendo) angina
- caused by
- warning sign?
- EKG /serology
progressively decreased activity levels = eventually get to pain at rest
- progressive increase in frequency, duration and severity of pain (>20 minutes)
- 90% obstruction of cross sectional area = inadequate perfusion at rest
Cause: disruption of plaque with superimposed thrombosis, embolus, and/or vasospasm
Forerunner of MI = imminent
EKG: +/- ST depression/T inversion
NO increase of cardiac anzymes
What is a MI?
- strong correlation?
death of cardiac muscle due to severe ischemia
strongly correlated to atherosclerosis
What is protective against myocardial infarction in women?
estrogen until menopause
Sequence of pathogenesis of MI:
1. plaque changes
2. sub-endothelial collagen exposed
4. coagulation cascade = thrombus occlusion of vessel
Myocardial response to ischemia
reduced production of ATP = lactic acid
contractility ceases within a minute of severe ischemia = myocyte death takes long (20-30 minutes)
>20-30 minutes = irreversible damage/necrosis of myocytes
What can confirm MI?
Where is ischemia most pronounced first? why?
more vulnerable (end of line)
Cardiac enzymes present during a myocardial infarction?
1. Troponin T or I (cTnT or cTnI)
- elevated for 6-10 days
**stays elevated after CK-MB returns to normal - not new event
has the most specificity for cardiac muscle,
elevated for 2-3 days
Clinical presentation of MI:
constricting, squeezing, pressure, choking,
Sometimes radiates to left arm and jaw
asymptomatic (10-25%) elderly and diabetics
- rapid, weak pulse, perfuse sweating
Transmural Myocardial infarction:
complete blockage of epicardial/cardiac vessel
Q wave exaggerated (more down) = myocardial death/cell necrosis
- remains on EKG, not time specific
ST elevation (STEMI)
area least perfused - most vulnerable
1/3 of wall thickness = not full thickness
resolves before full thickness necrosis can occur
EKG for subendocardial myocardial infarction:
absence of Q wave = non-Q wave MI
ST segment depression (NSTEMI)
Severe reduction in blood pressure (ie:shock) superimposed on non-critical coronary stenosis, will result in?
circumferential subendocardial infarct - not single artery distribution
global hypoperfusion = global subendocardial effect
Change timeline in MI:
0-4 hours: NO CHANGES
4-24 hours: in order of appearance
1. wavy fibers (3-12 with edema)
2. contraction band necrosis
3. early neutrophils (12-24 hours) - coagulation necrosis
- dense neutrophilic infiltrate (coagulation necrosis)
- macrophages and dead cells
- macrophages and granulation tissue
Acute MI of posterolateral LV
- what enzyme is preserved is some areas with nonexistent (leaked out) in other areas?
Lactate dehydrogenase preserved in non-infarcted myocardium
no LDH = white
What is seen in the myocardium 1 day post-infarct?
wavy fibers with edema + fluid in between
early coagulative necrosis (6-12 hours)
What does contraction band necrosis look like on histology?
loss of nuclei
seen within 4-24 hours
What does a 3 day old infarct look like on histology?
dense neutrophilic infiltrate
- most prominent 1-3 days
What does a 3-4 day old infarct look like on histology?
- cells presents?
3-10 days macrophages remove necrotic myocytes
What does granulation tissue look like post-infarct?
- when is it most prominent?
Loose collagen (blue fibers)
- trichrome stain
Most prominent at 1-2 weeks
Ischemic heart disease/coronary artery disease
1. angina pectoris
2. myocardial infection - ischemia causes frank myocyte necrosis
3. chronic IHD with heart failure/"ischemic cardiomyopathy"
4. sudden cardiac death (SCD) - unexpected death from cardiac causes
When does the myocardium stop contracting once ATP is depleted?
When does myocyte death begin when ATP is depleted?
After 2-3 hours of ATP depletion, what results in the myocardium?
myocyte death has occurred
- reperfusion here
- histology begins with the wavy fibers
During MI treatment, the goal is prompt ____.
"Time is myocardium"
1/2 of the deaths from a MI occurs in ___.
first hour (Arryhthmias)
- many don't get to the hospital
The first 3-4 hours of MI are critical, and is diagnosed by:
clinical, lab myocardial proteins, and EKG
Contractile dysfunction from MI
LV failure (hypotension, pulmonary congestion = pulmonary edema)
Cardiogenic shock - 70% mortality
Arryhthmia secondary to MI
arrhythmia is myocardial instability/conduction disturbances
most common cause of death within first few hours of MI
Myocardial rupture secondary to MI:
due to transmural necrosis
ventricle free wall - most common (anterolateral) 2-8 days after MI - wall is weakest and vulnerable
causes hemoperricardium and cardiac tamponade
Pericarditis secondary to MI:
- results (syndromes)
- timeline of occurrence
2-3 weeks to months post MI
- patient has friction rub on PE
fibrinous pericarditis (transmural)
- results possible
scar tissue bulges during systole = thrombus formation, arrhythmia, heart failure
Mural thrombus secondary to MI:
- how is a hx of MI related to this?
abnormal contractility = stasis
Hx of MI= can cause thrombus to embolus to brain or other organs/limbs
Papillary muscle rupture
- patient presentation
papillary muscle rupture = acute mitral regurgitation
new onset murmur post MI = papillary muscle problem ! ! ! !
Progressive late heart failure secondary to MI:
chronic ischemic heart disease
- factors to take into account
- compensatory mechanism
factors: infarct size, location and fraction of wall involved (transmural?)
overall 30% mortality first year and 3-4% each additional year
compensatory hypertrophy and dilation of non-infarcted myocytes
Ventricular remodeling is a result of:
- what are risks due to this compensation?
- hemodynamically helpful but can increase o2 demands = increased ischemia = decreased function
Major causes of death with MI complications:
1. cardiac arrhythmia - major cause in first few hours
2. cardiogenic shock
Sudden cardiac death
- caused by
death usually within one hour of developing symptoms
usually from lethal arrhythmia (v.fib)
How does sudden cardiac death happen?
1. 80% coronary artery disease
2. Cardiomyopathies - most common non-ischemic cause of sudden cardiac death
- dilated, alcoholic, idiopathic, fibrotic, or hypertrophic
[In reality] What is the most common cause of sudden cardiac death in patients that are younger than 35?
fatal arrhythmia in a structurally normal heart
What is the most common cause of sudden cardiac death in patients who are 14-24?
hypertrophic cardiomyopathy (HOCM)
- sudden unexplained death in young athletes
What is chronic ischemic heart disease clinically called?
progressive CHF from ischemic damage and/or inadequate compensation
How does chronic ischemic heart disease show up physically on the myocardium?
discreet scars of healed infarcts
myocardial hypertrophy and ventricle dilation
endocardium is patchy fibrosis due to abnormal wall shear forces from turbulent flow
Anterior Myocardial Rupture (pic)
Mural thrombus (pic)
Rupture with hemoperricardium (pic)
Left ventricular aneurysm
- what happens to the ventricle wall, and why?
bulging of the ventricular wall due to weakness from MI
What are some associated valvular disease?
1. aortic stenosis
2. mitral stenosis
3. mitral regurgitation (mitral valve prolapse)
What valvular problems are associated with rheumatic heart disease?
aortic stenosis, mitral stenosis
What are all valve defects at risk of developing?
What is the etiology of aortic stenosis?
congenital valve defect (bicuspid)
- wear and tear degenerative disease in elderly (calcific stenosis)
- scarring of rheumatic disease
What are the effects of aortic stenosis?
1. increased afterload
- syncope = poor blood flow to the brain
2. LV hypertrophy - working against increased pressure
- incomplete left ventricular filling
3. pulmonary congestion (backup into lung vasculature)
4. RV strain (pump against congestion)
What are symptoms of aortic stenosis?
Classic triad = dyspnea, syncope, angina
- harsh systolic ejection murmur (R 2nd intercostal) radiating to the carotids
What is the cause of calcific aortic stenosis?
- clinical presentation
wear and tear - dystrophic calcification
demographic: 2% of population - seen in elderly
- angina on exertion, dyspnea or CHF
If there is an elderly patient with syncopal episodes, what is the most likely diagnosis?
Calcific aortic stenosis is associated with ____.
- congenital bicuspid valve (50%)
- rheumatic heart disease
Hypertrophic obstructive cardiomyopathy (HOCM)
Idiopathic hypertrophic subaortic stenosis (IHSS)
Beta myosin heavy chain gene mutation
hyper contractile heart muscle with poorly compliant left ventricle
= abnormal diastolic filling, systolic function is ok
- where is the obstruction?
usually asymmetric septal hypertrophy (free wall less) without dilation
left ventricular outflow obstruction
- subaortic thickening
LV thick walled and heavy associated with HOCM and IHSS:
1. massive myocyte hypertrophy
2. myofiber bundle disarray '
3. interstitial fibrosis
What does hypertrophic cardiomyopathy look on histology?
myocyte hypertrophy and myofiber bundle disarray
- myocytes not arranged properly
Restrictive cardiomyopathy is:
decrease in ventricular compliance, impaired ventricular filling during diastole
- infiltrating diseases, radiation fibrosis or scarring
Causes of restrictive cardiomyopathy
3. endocardial fibroelastosis - thickening of LV during first 2 years of life
- looks like endocardium covered in thick white cheese
deposition of proteins in organs and tissues
Congo Red + polarization = Apple green birefringence
Endocardial fibroelastosis is commonly seen in which patients?
fibrosis of endocardium in infants and young children
What is the most common cause of myocarditis?
- Coxsackie A and B
- can lead to dilated cardiomyopathy
If myocarditis is caused by a parasitic infection, what is the disease at risk?
Trypanomas cruzi (Chagas disease)
- parasites of myofibers
- can get myocarditis that leads to cardiac insufficiency in 10-20 years
If myocarditis is caused by hypersensitivity, what type of inflammation presents?
Giant cell myocarditis
multi-nucleate giant cells, end stage myocarditis = poor prognosis
Cardiotoxic drugs causing myocarditis:
Myocarditis can be _____, and cause __ or evolve into _______
asymptomatic; cause acute heart failure or evolve into dilated cardiomyopathy
lymphocytic infiltrates between myocytes
"Lymphocytes between myoocyte bundles" = VIRAL
serious transudate in pericardial space
- from any condition causing edema (CHF, nephrotic syndrome)
accumulation of blood in the pericardial sac
- traumatic perforation of heart, aortic dissection, post-MI
Acute pericarditis is usually caused by:
- common type
usually idiopathic or viral cause
1. serous pericarditis - viral
Acute pericarditis symptoms
sharp piercing pain in center or left chest = worse with inspiration or cough
Pericardial friction rub - 85% lower left sternal border (grating, scratching)
SOB with reclining
- relief sitting up and leaning forward
Acute serous pericarditis
- fluid characteristics
viral, SLE, rheumatic fever
serous = clear, straw colored, protein rich exudate
- suppurative type characteristics
- cloudy inflammatory exudate or pus
- Staph, Strep, Pneumococcus (pneumonia), some fungal infections
scarring = constrictive pericarditis
- associated diseases
blood inflammatory exudate
most common= tumor infiltration
fibrin rich exudate
- uremia, myocardial infarction, rheumatic fever
direct extension of TB in tracheobronchial lymph nodes
- prevalence / origin
rare and almost always viral origin
- most frequent precursors "RUMS"
pericarditis secondary to another disease/disorder
Radiation (chest) or Rheumatic fever
Systemic lupus erythematous
composed of fibrinous/serous exudate
What are types of chronic pericarditis?
1. adhesive mediastinopericarditis
2. constrictive pericarditis
- predisposing factors
- what happens to the pericardial sac?
may follow infectious pericarditis, previous cardiac surgery, or irradiation of mediastinum
sac is obliterated and pericardium adheres to adjacent structure = functional stressors
cardiac hypertrophy and dilation
- sac characteristics
heart encased in a dense, fibrous, fibrocalcific scar that limits diastolic expansion and cardiac output
mimics restrictive cardiomyopathy
What are some primary benign tumors of the heart?
1. Myxoma - most common
2. Fibroma - fibrous
3. Lipoma - tumor of fat
4. Rhabdomyomas - most common primary tumor pediatric heart
What is the most common malignant primary tumor of the heart?
most common primary tumor of the heart - benign
1cm - 10cm in size
- commonly in the left atrium (fossa ovalis)
- mucopolysaccharide matrix with focal vessels and gland structures
- can embolize or cause fever and malaise (IL-6)
- associated disease
most frequent primary tumor of the heart in infants and children
associated with tuberous sclerosis - TSC1 or TSC2 tumor suppressor gene (50%)
often regress spontaneously (Hamartoma)
Spider cells seen microscopically
What type of tumors are more frequent than primary tumors?
1. carcinoma of the breast
2. bronchogenic carcinoma
Carcinoid heart disease
- what is it
- commonly affected site
cardiac manifestations caused by bioactive compounds
GI carcinoid with hepatic metastasis
Right side of heart affected (lung capillary bed protects the left heart = intimal plaque-like thickening = subendocardial fibrosis of the right heart
Associated finding from carcinoid syndrome (Sx)
- episodic cutaneous flushing
- elevated serum Serotonin (5HT) and urine metabolite (5-HIAA) - follow disease severity
- causative agent
SX: fever, Janeway lesions, Osler nodes
ACUTE: highly virulent and destructive
previously normal vales
death can occur within days to weeks
IV drug users (tricuspid, pulmonic)
- causative agent
Subacute = less virulent, less destructive course
- previously damaged valves
- Streptococcus viridans (50-60%)
Non infective thrombotic (Marantic) endocarditis
- clinical presentation
- serum levels
malnourished and cancer patients (especially adenocarcinoma)
STERILE clots on valve - not destructive
presents as new onset stroke in a cancer patient
Blood cultures are negative
What is cardiomyopathy?
Non-inflammatory disorders of the myocardium; not caused by HTN, Congenital heart disease, valve disease or CAD
What is the typical patient who would be presenting with cardiomyopathy?
younger age of the patient and progressive deterioration
- likely causes
- associated mutations
usually unknown cause, but alcoholism, viral, and drugs can cause it
- can be associated with certain protein mutations
- best example
infiltrative process within the myocardium = stiffening of the heart muscle - interfere with proper pumping/contraction
Best example = cardiac amyloidosis
- effects seen on the heart
AD inheritance (different protein mutations)
hypertrophy of all chamber walls especially the septum
disoriented, tangled, and hypertrophies myocardial fibrils
Types of pulmonary HTN:
- defining characteristic of each
1. Left heart failure type
- "pulmonary venous HTN" due to increased volume
2. Hypoxia induced
- constrict areas not being well ventilated to maintain V/Q ratio
- improve with O2
3. Remodeling type "pulmonary arterial hypertension"
- irreversible = deadly
- can be end result of #1 or #2 or anything that causes congestion/volume over time
Congenital Cardiac malformations with cyanosis:
Tetralogy of Fallot
Transposition of the great arteries
Total anomalous pulmonary venous return (connection)
What is the most common type of heart disease in children?
Congenital heart disease (CHD)
multifactorial factors; etiology only in 10% of cases
- sporadic genetic abnormalities are major known causes
What are some major congenital defect categories?
1. obstructive defects
2. shunt defects
Patent ductus arteriosus may be needed in congenital heart defects for _____
- what can be used for this?
Prostaglandins delay closure
Indomethacin promotes closure
Right to Left shunt vs. Left to Right shunt:
Left to right = non-cyanotic
Right to left = cyanotic
Obstructive congenital heart disease
- results on heart muscle
coarctation of the aorta, aortic valvular stenosis, and pulmonary valvular stenosis produce abnormal narrowing of chambers
-complete obstruction is called atresia
may cause low volume and low muscle mass
In obstructive congenital heart disease, when would hypoplasia occur vs. atrophy?
hypoplasia = occurs before birth
atrophy = develops postnatally
What is the most common congenital heart disease, with a left to right shunt?
- results on the heart
- results long term
***ventricular septal defect
chronic elevation of pulmonary pressures = pulmonary HTN
- medial hypertrophy and vasoconstriction on pulmonary vasculature
Can lead to long term permanent changes seen in systemic htn
- atherosclerotic lesions
- right ventricular hypertrophy
Right to left shunt congenital heart disease
- clinical presentation
- causes of ___ heart disease:
Right --> Left = cyanosis from early on
- creates hypoxemia and dusky blue skin/mucus membranes
- paradoxical embolism
- hypertrophic osteoarthropathy
- polycythemia = due to chronic low o2 levels
Causes of cyanotic heart disease (5T's)
Large left --> right shunt that increases ___ blood flow.. = __ HTN = __ RV pressure = ___ to ___ shunt
increased RV pressure
right to left shunt (SWITCH)
What is the syndrome that develops when a large left --> right shunt becomes a right --> left shunt over time?
- is there cyanosis?
What are causes of the left to right shunt?
VSD, ASD, PDA
How do the patients with a left to right shunt present?
- what is the cause of their presentation??
start out ok (pink) then eventually with time and increased pulmonary HTN they get blue
due to Pulmonary HTN ***
- have a murmur that is untreated --> fatigue, cyanosis
Ventricular septal defect (VSD)
- pathology of the shunts:
- presentation in childhood:
most common overall type of CHD
- if in pediatrics, there are likely other anomalies
- adults, it is likely isolated defect
1. Membranous VSD = usually single and large (90%_ = most common congenital heart disease
2. Muscular = small and multiple = can close spontaneously via proliferation of cardiac stem cells
starts as left-right shunt = increased pulmonary blood flow = RV hypertrophy
reversal of shunt = tardive cyanosis (Eisenmenger complex)
***presents with a holosystolic/pansystolic murmur
Atrial septal defect (ASD)
incomplete tissue formation
communication of blood between left and right atria
usually asymptomatic until adulthood
NOT same as patent foramen ovale since FO is not considered a congenital defect
What is the most common CHD discovered in adults?
- pathology of this
- heart sounds
Left - right shunt due to P gradient and RV compliance
Right side atrial overload = increased pulmonary blood flow
murmur from excess pulmonary valve flow or flow through ASD
fixed S2 split of heart sounds (delayed closure of pulmonic valve) = delayed closure due to increased RV volume
generally well tolerated - often asymptomatic before age 30
What are some different ASD classifications?
1. Septum secundum deficient growth = Secundum ASD
most common type
- usually not associated with other abnormalities
2. Ostium primum = seen in Down syndrome - due to endocardial cushion defects
3. Sinus venosum = near entrance of SVC
Patent ductus arteriosus
- intrauterine function
- newborn function
intrauterine = blood flow can bypass unoxygenated lungs
newborn = closes in 1-2 days, complete obliteration = ligamentum arteriosum
- closes due to oxygenation, reduced prostaglandin E2 (natural), lower pulmonary pressure (first breath)
Result of delayed closure of the patent ductus arteriosus
congenital defects - VSD (increased pulmonary P)
complete transposition of the great vessels
tetralogy of fallot
Clinical presentation of patent ductus arteriosus:
- shunt type
- heart sounds?
machinery murmur throughout systole and diastole
initially left -- right shunt = no cyanosis
- large shunts = increased pulmonary pressure = HTN = reversal of shunt
Congenital malformation, ____ _____ _____, may be life saving.
- which drugs are associated with this process?
Patent ductus arteriosus may be life saving
1. Prostaglandin = delays closure
2. Indomethacin = promotes closure
Tetralogy of Fallot
key characteristics that classify TOF
What determines the prognosis?
most common form of cyanotic CHD = NOT CH2 signaling pathway
1. Subpulmonic (infundibular) stenosis (most common) or valvular stenosis
2. Dextraposition of the aorta
4. RV hypertrophy (secondary)
degree of pulmonic/ subpulmonic stenosis: determines prognosis
What is the problem and solution to Tetralogy of Fallot:
- restriction of blood flow into the pulmonary artery due to stenosis = minimal amount of blood getting oxygenated
- if stenosis is severe they must have PDA (patent ductus arteriosus) to get blood to pulmonary artery to get blood oxygenated
VSD allows blood entering right heart to get to the left heart (otherwise minimal return from pulmonary vein into LA)
What are the clinical findings in a patient with Tetralogy of Fallot?
****boot-shape heart on x-ray - from right ventricular hypertrophy
- can have complete atresia of pulmonary valve/arteries
= blood flow through PDA and/or dilated bronchial arteries = survival
right sided aortic arch present in 25%
- infective endocarditis
- cerebral abscess
- secondary polycythemia increasing likelihood of thrombosis
- clubbing of the fingers (cyanosis)
What are the outcomes of tetralogy of fallot?
depends on the extent of pulmonary obstruction
mild sub-pulmonary stenosis = right shunt (like VSD) = pink tetralogy
more severe RV outflow obstruction= right - left shunt = cyanosis
MOST = cyanotic soon after birth
What are tet spells?
cyanotic with crying, fever, hypotension --> squatting reverses the shunt
- subpulmonic stenosis protects from pressure overload = no right sided heart failure
pressure relieved from shunt to LV and aorta
What is the most common form of transposition of the great vessels?
problem associated with TGA
1. aorta - arises from the RV
2. pulmonary artery - arises from the LV
- RA/ventricle receives venous blood and pumps venous blood into aorta and LA/ventricle receives oxygenated blood and pumps it back into the lungs
2 separate system (systemic + pulmonic) = not compatible with life!!
Solution to transposition of the great vessels.
survival requires a PDA or septal defect (to have mixed systems for o2 to get to tissues)
Heart characteristics of patients with transposition of the great vessels:
- associated abnormalities
- physical properties of the heart
65% have patent forman ovale or ductus arteriosis
need shunt to survive (keep open with prostaglandins)
RV hypertrophy prominent because supplies systemic circulation
Heart shaped like an egg
Truncus arteriosus is the failure to separate the truncus arteriosus into the ___ and ______
- blood received into ___
- clinical presentation
- blood flow effect?
aorta and pulmonary artery
blood received into a single great artery (like an elephant trunk)
presence of early cyanosis - mixed blood anyways
increased pulmonary blood flow
Tricuspid atresia is the complete ___ of the tricuspid valve orifice.
- Associated with:
- hypoplastic RV
- atrial septal defect
problem: no tricuspid valve = no blood to RV or pulmonary system = no oxygenation of blood
solution: Must have ASD or VSD to allow blood to circulate through other chambers into RV
In which anomaly do all four pulmonary veins connect to the SVC?
total anomalous pulmonary venous return
- dumping into the venous side and not returning to the LA
- clinical Sx
- disease associated
proximal to PDA
PDA supplies deoxy blood to lower extremities because of lower aortic pressure after coarctation
- early cyanosis in lower extremities only
- HTN in upper extremities
- LV hypertrophy
- Difference in upper/lower BP - weak distal pulse
Associated with Turner syndrome
- Clinical manifestations
- HTN involving upper extremities
- diminished or absent femoral pulses, cold lower extremities
- LV hypertrophy
- difference in upper and lower BP
- notching ribs on xray
What is the most common CHD overall?
- then ASD, PDA
What is the most common cyanotic CHD, while the patient is generally not cyanotic at birth?
Tetralogy of Fallot
What is the most common CHD with cyanosis immediately at birth?
Transposition of the great vessels
(PDA needs to remain open)
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